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{{distinguish|PKCS{{!}}PKCS#9}}
[[File:PCSK9.png|200px|thumb|right|Structure of the PCSK9 protein]]
{{Infobox_gene}}
{{SI}}
'''Proprotein convertase subtilisin/kexin type 9''' ('''PCSK9''') is an [[enzyme]] encoded by the ''PCSK9'' [[gene]] in humans on [[Chromosome 1 (human)|chromosome 1]].<ref name="Seidah_2003" /> It is the 9th member of the [[proprotein convertase]] family of proteins that activate other proteins.<ref name="pmid26040332">{{cite journal | vauthors=Zhang L, Song K, Zhu M, Shi J, Zhang H, Xu L, Chen Y | title=Proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, atherosclerosis and ischemic stroke | journal= [[International Journal of Neuroscience]] | volume=126 | issue=6 | pages=675-680 | year=2016 | doi= 10.3109/00207454.2015.1057636 | PMID = 26040332 }}</ref> Similar genes ([[ortholog]]s) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; [[proprotein convertase]]s remove that section to activate the enzyme.<ref name="Lagace_2014" /> The ''PCSK9'' gene also contains one of 27 [[Locus (genetics)|loci]] associated with increased risk of [[coronary artery disease]].<ref name="Mega_2015">{{cite journal | vauthors = Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS | title = Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials | journal = Lancet | volume = 385 | issue = 9984 | pages = 2264–71 | date = June 2015 | pmid = 25748612 | pmc = 4608367 | doi = 10.1016/S0140-6736(14)61730-X }}</ref>
{{CMG}}


==Overview==
PCSK9 is ubiquitously expressed in many tissues and cell types.<ref>{{cite web|url=http://biogps.org/#goto=genereport&id=255738|title=BioGPS - your Gene Portal System|website=biogps.org|access-date=2016-08-19}}</ref> PCSK9 binds to the receptor for [[low-density lipoprotein]] particles (LDL), which typically transport 3,000 to 6,000 fat molecules (including [[cholesterol]]) per particle, within [[extracellular fluid]]. The [[LDL receptor]] (LDLR), on [[liver]] and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells, thus reducing LDL particle concentrations. If PCSK9 is blocked, more LDLRs are recycled and are present on the surface of cells to remove LDL-particles from the extracellular fluid.<ref>{{cite journal | vauthors = Weinreich M, Frishman WH | title = Antihyperlipidemic therapies targeting PCSK9 | journal = Cardiology in Review | volume = 22 | issue = 3 | pages = 140–6 | date = 2014 | pmid = 24407047 | doi = 10.1097/CRD.0000000000000014 }}</ref> Therefore, blocking PCSK9 can lower blood LDL-particle concentrations.<ref name="url_ms_harvard">{{cite web | url = http://sitn.hms.harvard.edu/flash/2015/a-potential-new-weapon-against-heart-disease-pcsk9-inhibitors/ | title = A potential new weapon against heart disease: PCSK9 inhibitors | work = Science in the News | publisher = Harvard University | date = 2015-05-18 | first = Mary E. | last = Gearing | name-list-format = vanc }}</ref><ref name="Joseph_2015">{{cite journal | vauthors = Joseph L, Robinson JG | title = Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy | journal = Progress in Cardiovascular Diseases | volume = 58 | issue = 1 | pages = 19–31 | year = 2015 | pmid = 25936907 | doi = 10.1016/j.pcad.2015.04.004 }}</ref>
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is a serine protease encoded by the PCSK9 gene. PCSK9 has a medical significance because it plays an important role in lipid homeostasis by promoting degradation of the [[LDL receptor]]s responsible for clearing circulating [[LDL-cholesterol]] (LDL-C) from the plasma. Therefore, drugs that inhibit the actions of PCSK9 can theoretically lower the circulating cholesterol level, and thus lower the risk of developing cardiovascular disease.


==Historical Perspective==
PCSK9 has medical importance because it acts in lipoprotein [[homeostasis]]. Agents which block PCSK9 can lower LDL particle concentrations. The first two PCSK9 inhibitors, [[alirocumab]] and [[evolocumab]], were approved as once every two week injections, by the U.S. Food and Drug Administration in 2015 for lowering LDL-particle concentrations when [[statin]]s and other drugs were not sufficiently effective or poorly tolerated. The cost of these new medications, {{as of|2015|lc=y}}, was $14,000 per year at full retail; judged of unclear cost effectiveness by some.<ref name="Hlatky_2017">{{cite journal | vauthors = Hlatky MA, Kazi DS | title = PCSK9 Inhibitors: Economics and Policy | journal = Journal of the American College of Cardiology | volume = 70 | issue = 21 | pages = 2677–2687 | year = 2017 | pmid = 29169476 | doi = 10.1016/j.jacc.2017.10.001 }}</ref>  While these medications are prescribed by many physicians, the payment for prescriptions are often denied by insurance providers.<ref name="NYT2018">Gina Kolata, [https://www.nytimes.com/2018/10/02/health/pcsk9-cholesterol-prices.html "These Cholesterol-Reducers May Save Lives. So Why Aren’t Heart Patients Getting Them?"], ''The New York Times'', Oct. 2, 2018. Retrieved 5 October 2018.</ref><ref name="pmid28328015">{{cite journal | vauthors = Baum SJ, Toth PP, Underberg JA, Jellinger P, Ross J, Wilemon K | title = PCSK9 inhibitor access barriers-issues and recommendations: Improving the access process for patients, clinicians and payers | journal = Clinical Cardiology | volume = 40 | issue = 4 | pages = 243–254 | year = 2017 | pmid = 28328015 | pmc = 5412679 | doi = 10.1002/clc.22713 }}</ref><ref name="pmid28973087">{{cite journal | vauthors = Navar AM, Taylor B, Mulder H, Fievitz E, Monda KL, Fievitz A, Maya JF, López JA, Peterson ED | title = Association of Prior Authorization and Out-of-pocket Costs With Patient Access to PCSK9 Inhibitor Therapy | journal = JAMA Cardiology | volume = 2 | issue = 11 | pages = 1217–1225 | year = 2017 | pmid = 28973087 | doi = 10.1001/jamacardio.2017.3451 | laysummary = https://www.reuters.com/article/us-health-cholesterol-medication/insurers-are-slow-to-approve-pricey-new-cholesterol-drugs-idUSKBN1C92XF | laysource = Thomson Reuters }}</ref>
PCSK9 was initially described as neural apoptosis-regulated convertase-1 (NARC-1), which is expressed in cells that have the capacity to proliferate and differentiate such as hepatocytes, kidney mesenchymal cells, colon epithelial cells, and embryonic brain telencephalon neurons.<ref name="Seidah-2003">{{Cite journal | last1 = Seidah | first1 = NG. | last2 = Benjannet | first2 = S. | last3 = Wickham | first3 = L. | last4 = Marcinkiewicz | first4 = J. | last5 = Jasmin | first5 = SB. | last6 = Stifani | first6 = S. | last7 = Basak | first7 = A. | last8 = Prat | first8 = A. | last9 = Chretien | first9 = M. | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. | journal = Proc Natl Acad Sci U S A | volume = 100 | issue = 3 | pages = 928-33 | month = Feb | year = 2003 | doi = 10.1073/pnas.0335507100 | PMID = 12552133 }}</ref>  The function of PCSK9 was first described in 2003 when a gain-of-function mutation of PCSK9 gene (leading to increased activity) was associated with [[familial hypercholesterolemia]] in 4 french families.<ref name=abifadel>{{cite journal | author = Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C | title = Mutations in PCSK9 cause autosomal dominant hypercholesterolemia | journal = Nat. Genet. | volume = 34 | issue = 2 | pages = 154–6 | year = 2003 | month = June|pmid = 12730697 | doi = 10.1038/ng1161 }}</ref> The association was further clarified in 2005 after the discovery of loss-of-function mutations of PCSK9 in patients with low [[LDL-C]]. This loss-of-function was linked to a 40% reduction in plasma levels of [[LDL-C]] in the studied population.<ref name="Cohen-2005">{{Cite journal | last1 = Cohen | first1 = J. | last2 = Pertsemlidis | first2 = A. | last3 = Kotowski | first3 = IK. | last4 = Graham | first4 = R. | last5 = Garcia | first5 = CK. | last6 = Hobbs | first6 = HH. | title = Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. | journal = Nat Genet | volume = 37 | issue = 2 | pages = 161-5 | month = Feb | year = 2005 | doi = 10.1038/ng1509 | PMID = 15654334 }}</ref>


==Biochemistry==
=== History ===
===Structure===
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease encoded by the PCSK9 [[gene]] in humans.<ref name=seidah>{{cite journal | author = Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 3 | pages = 928–33 | year = 2003 | month = February | pmid = 12552133 | pmc = 298703 |doi = 10.1073/pnas.0335507100 }}</ref>  PCSK9 is a 692 amino acid protein that is expressed mainly in the liver, intestine, and kidney.<ref name="Zaid-2008">{{Cite journal  | last1 = Zaid | first1 = A. | last2 = Roubtsova | first2 = A. | last3 = Essalmani | first3 = R. | last4 = Marcinkiewicz | first4 = J. | last5 = Chamberland | first5 = A. | last6 = Hamelin | first6 = J. | last7 = Tremblay | first7 = M. | last8 = Jacques | first8 = H. | last9 = Jin | first9 = W. | title = Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. | journal = Hepatology | volume = 48 | issue = 2 | pages = 646-54 | month = Aug | year = 2008 | doi = 10.1002/hep.22354 | PMID = 18666258 }}</ref>  PCSK9 gene encodes a [[proprotein convertase]] belonging to the [[proteinase K]] subfamily of the secretory subtilase family.  The encoded protein is synthesized as a soluble [[zymogen]] that undergoes autocatalytic intramolecular processing in the [[endoplasmic reticulum]].  The protein may function as a [[proprotein convertase]], and also plays a major regulatory role in [[cholesterol]] homeostasis.


===Regulation===
In February 2003, [[Nabil Seidah]], a scientist at the Clinical Research Institute of Montreal in Canada, discovered a novel human [[proprotein convertase]], the gene for which was located on the short arm of [[chromosome 1]].<ref name=NatureNews2013>{{cite journal | vauthors = Hall SS | title = Genetics: a gene of rare effect | journal = Nature | volume = 496 | issue = 7444 | pages = 152–5 | date = April 2013 | pmid = 23579660 | doi = 10.1038/496152a | bibcode = 2013Natur.496..152H }}</ref> Meanwhile, a lab led by Catherine Boileau at the [[Necker-Enfants Malades Hospital]] in Paris had been following families with [[familial hypercholesterolaemia]], a genetic condition that, in 90% of cases causes [[coronary artery disease]] (FRAMINGHAM study) and in 60% of cases may lead to an early death;<ref name="pmid11325764">{{cite journal | vauthors = Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ | title = Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study | journal = BMJ (Clinical Research Ed.) | volume = 322 | issue = 7293 | pages = 1019–23 | year = 2001 | pmid = 11325764 | pmc = 31037 | doi = 10.1136/bmj.322.7293.1019 }}</ref> they had identified a mutation on chromosome 1 carried by some of these families, but had been unable to identify the relevant gene. The labs got together and by the end of the year published their work, linking mutations in the gene, now identified as PCSK9, to the condition.<ref name="Abifadel_2003"/><ref name=NatureNews2013/> In their paper, they speculated that the mutations might make the gene overactive. In that same year, investigators at [[Rockefeller University]] and [[University of Texas Southwestern]] had discovered the same protein in mice, and had worked out the novel [[Protein–protein interaction#Protein–protein interaction networks|pathway]] that regulates [[LDL cholesterol]] in which PCSK9 is involved, and it soon became clear that the mutations identified in France led to excessive PCSK9 activity, and thus excessive removal of the LDL receptor, leaving people carrying the mutations with too much LDL cholesterol.<ref name=NatureNews2013/> Meanwhile, Dr. Helen H. Hobbs and Dr. Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples.<ref name="Joshi2014">Parag H. Joshi, Seth S. Martin, and Roger S. Blumenthal, "[https://www.healio.com/cardiology/chd-prevention/news/print/cardiology-today/%7Bd531fcd9-ea52-4230-b412-da9270344fff%7D/the-fascinating-story-of-pcsk9-inhibition-insights-and-perspective-from-acc The fascinating story of PCSK9 inhibition: Insights and perspective from ACC]", ''Cardiology Today'', May 2014. Retrieved 5 October 2018.</ref> With the new knowledge about the role of PCSK9 and its location in the genome, they sequenced the relevant region of chromosome 1 in people with very low cholesterol and they found [[nonsense mutations]] in the gene, thus validating PCSK9 as a [[biological target]] for [[drug discovery]].<ref name=NatureNews2013/><ref name="pmid25052769">{{cite journal | vauthors = Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M, Moussalli ML, Rabès JP, Varret M, Boileau C | title = Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs | journal = Current Atherosclerosis Reports | volume = 16 | issue = 9 | page = 439 | date = September 2014 | pmid = 25052769 | doi = 10.1007/s11883-014-0439-8 }}</ref>
PCSK9 and LDL receptors are both mainly regulated by the transcription factor sterol-responsive element-binding protein 2 (SREBP2).  SREBP2 is involved in a pathway also induced by statins<ref name="Lambert-2007">{{Cite journal | last1 = Lambert | first1 = G. | title = Unravelling the functional significance of PCSK9. | journal = Curr Opin Lipidol | volume = 18 | issue = 3 | pages = 304-9 | month = Jun | year = 2007 | doi = 10.1097/MOL.0b013e3281338531 | PMID = 17495605 }}</ref> and by experimental [[resistin]]<ref name="Melone-2012">{{Cite journal | last1 = Melone | first1 = M. | last2 = Wilsie | first2 = L. | last3 = Palyha | first3 = O. | last4 = Strack | first4 = A. | last5 = Rashid | first5 = S. | title = Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. | journal = J Am Coll Cardiol | volume = 59 | issue = 19 | pages = 1697-705 | month = May | year = 2012 | doi = 10.1016/j.jacc.2011.11.064 | PMID = 22554600 }}</ref> which is an adipose-tissue derived adipokine.  Another regulator of the PCSK9 gene expression is the hepatic nuclear factor 1 alpha (HNF1a), a transcription factor activated in the liver cells.<ref name="Dong-2010">{{Cite journal  | last1 = Dong | first1 = B. | last2 = Wu | first2 = M. | last3 = Li | first3 = H. | last4 = Kraemer | first4 = FB. | last5 = Adeli | first5 = K. | last6 = Seidah | first6 = NG. | last7 = Park | first7 = SW. | last8 = Liu | first8 = J. | title = Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. | journal = J Lipid Res | volume = 51 | issue = 6 | pages = 1486-95 | month = Jun | year = 2010 | doi = 10.1194/jlr.M003566 | PMID = 20048381 }}</ref>


==Physiologic Function==
In July 2015, the [[Food and Drug Administration|FDA]] approved the first PCSK9 Inhibitor drugs for medical use.<ref>{{cite web|title = FDA approves Praluent to treat certain patients with high cholesterol|url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm|website = www.fda.gov|accessdate = 2015-07-26}}</ref>
===Lipid Homeostasis===
PCSK9 plays a major role in the metabolism of cholesterol.  It binds to the epidermal growth factor-like repeat A (EGF-A) domain of the [[low-density lipoprotein]] receptor (LDLR), inducing LDLR endocytosis and degradation in lysosomes.  Reduced LDL receptor levels result in decreased metabolism of [[low density lipoprotein]] (LDL) and increased levels of circulating LDL.<ref name=uendo>*{{cite web | url =http://www.uendocrine.com/presentations/hyperlipidemia/the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol| title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol | author = | authorlink = | coauthors = | date = 2012-11-11 }}</ref>  The [[Sterol regulatory element binding protein|sterol regulatory element-binding protein-2 (SREBP-2)]], which is activated in the presence of low intracellular levels of cholesterol, induces the expression of PCSK9. This leads to a decrease in LDL cholesterol metabolism thereby restoring normal levels of circulating.<ref name="Maxwell-2003">{{Cite journal  | last1 = Maxwell | first1 = KN. | last2 = Soccio | first2 = RE. | last3 = Duncan | first3 = EM. | last4 = Sehayek | first4 = E. | last5 = Breslow | first5 = JL. | title = Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. | journal = J Lipid Res | volume = 44 | issue = 11 | pages = 2109-19 | month = Nov | year = 2003 | doi = 10.1194/jlr.M300203-JLR200 | PMID = 12897189 }}</ref>
[[File:PCSK9 function 01.jpg|800px|center|PCSK9 function]]


<center><font size="1">''Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408''<ref name="Urban-2013">{{Cite journal  | last1 = Urban | first1 = D. | last2 = Pöss | first2 = J. | last3 = Böhm | first3 = M. | last4 = Laufs | first4 = U. | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. | journal = J Am Coll Cardiol | volume = 62 | issue = 16 | pages = 1401-8 | month = Oct | year = 2013 | doi = 10.1016/j.jacc.2013.07.056 | PMID = 23973703 }}</ref></font></center>
== Structure ==
=== Gene ===
The ''PCSK9'' gene resides on chromosome 1 at the band 1p32.3<ref>[https://ghr.nlm.nih.gov/gene/PCSK9#location PCSK9 gene - Genetics Home Reference<!-- Bot generated title -->]</ref> and includes 13 [[exon]]s.<ref name="ncbi.nlm.nih.gov">{{cite web|url=https://www.ncbi.nlm.nih.gov/gene/255738|title=PCSK9 proprotein convertase subtilisin/kexin type 9 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-08-19}}</ref> This gene produces two [[isoforms]] through [[alternative splicing]].<ref name="UniProt_Q8NBP7">{{cite web|url=https://www.uniprot.org/uniprot/Q8NBP7|title=PCSK9 - Proprotein convertase subtilisin/kexin type 9 precursor - Homo sapiens (Human) - PCSK9 gene & protein|website=www.uniprot.org|access-date=2016-08-19}}</ref>


In addition to lowering LDL-C, PCSK9 deficiency has also been shown to lower cardiovascular risk factors by reducing postprandial [[hypertriglyceridemia]].<ref name="Le May-2009">{{Cite journal  | last1 = Le May | first1 = C. | last2 = Kourimate | first2 = S. | last3 = Langhi | first3 = C. | last4 = Chétiveaux | first4 = M. | last5 = Jarry | first5 = A. | last6 = Comera | first6 = C. | last7 = Collet | first7 = X. | last8 = Kuipers | first8 = F. | last9 = Krempf | first9 = M. | title = Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. | journal = Arterioscler Thromb Vasc Biol | volume = 29 | issue = 5 | pages = 684-90 | month = May | year = 2009 | doi = 10.1161/ATVBAHA.108.181586 | PMID = 19265033 }}</ref> PCSK9-deficient mice have also been demonstrated to have reduced lymphatic apoB secretion (the major lipoprotein of chylomicrons and LDL) as well as an increased ability to clear [[chylomicrons]].<ref name="Sun-2012">{{Cite journal  | last1 = Sun | first1 = H. | last2 = Samarghandi | first2 = A. | last3 = Zhang | first3 = N. | last4 = Yao | first4 = Z. | last5 = Xiong | first5 = M. | last6 = Teng | first6 = BB. | title = Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. | journal = Arterioscler Thromb Vasc Biol|volume = 32 | issue = 7 | pages = 1585-95 | month = Jul | year = 2012 | doi = 10.1161/ATVBAHA.112.250043 | PMID = 22580899 }}</ref>
=== Protein ===
PCSK9 is a member of the [[Peptidase S|peptidase S8]] family.<ref name="UniProt_Q8NBP7" />


===Inflammation===
The solved structure of PCSK9 reveals four major components in the pre-processed protein: the [[signal peptide]] ([[Amino acid|residues]] 1-30); the [[N-terminus|N-terminal]] prodomain (residues 31-152); the [[catalytic domain]] (residues 153-425); and the [[C-terminal domain]] (residues 426-692), which is further divided into three modules.<ref name="Du_2011">{{cite journal | vauthors = Du F, Hui Y, Zhang M, Linton MF, Fazio S, Fan D | title = Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein | journal = The Journal of Biological Chemistry | volume = 286 | issue = 50 | pages = 43054–61 | date = December 2011 | pmid = 22027821 | pmc = 3234880 | doi = 10.1074/jbc.M111.273474 }}</ref> The N-terminal prodomain has a flexible crystal structure and is responsible for regulating PCSK9 function by interacting with and blocking the catalytic domain, which otherwise binds the [[epidermal growth factor]]-like repeat A (EGF-A) domain of the LDLR.<ref name="Du_2011" /><ref>{{cite journal | vauthors = Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, Ni YG, Hubbard B, Sitlani A, Carfí A | title = Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH | journal = EMBO Reports | volume = 12 | issue = 12 | pages = 1300–5 | date = December 2011 | pmid = 22081141 | pmc = 3245695 | doi = 10.1038/embor.2011.205 }}</ref><ref>{{cite journal | vauthors = Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP | title = The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol | journal = Structure | volume = 15 | issue = 5 | pages = 545–52 | date = May 2007 | pmid = 17502100 | doi = 10.1016/j.str.2007.04.004 }}</ref> While previous studies indicated that the C-terminal domain was uninvolved in binding LDLR,<ref>{{cite journal | vauthors = Bottomley MJ, Cirillo A, Orsatti L, Ruggeri L, Fisher TS, Santoro JC, Cummings RT, Cubbon RM, Lo Surdo P, Calzetta A, Noto A, Baysarowich J, Mattu M, Talamo F, De Francesco R, Sparrow CP, Sitlani A, Carfí A | title = Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants | journal = The Journal of Biological Chemistry | volume = 284 | issue = 2 | pages = 1313–23 | date = January 2009 | pmid = 19001363 | doi = 10.1074/jbc.M808363200 }}</ref><ref>{{cite journal | vauthors = Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J | title = Molecular basis for LDL receptor recognition by PCSK9 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 6 | pages = 1820–5 | date = February 2008 | pmid = 18250299 | pmc = 2538846 | doi = 10.1073/pnas.0712064105 | bibcode = 2008PNAS..105.1820K }}</ref> a recent study by Du et al. demonstrated that the C-terminal domain does bind LDLR.<ref name="Du_2011" /> The secretion of PCSK9 is largely dependent on the autocleavage of the signal peptide and N-terminal prodomain, though the N-terminal prodomain retains its association with the catalytic domain. In particular, residues 61-70 in the N-terminal prodomain are crucial for its autoprocessing.<ref name="Du_2011" />
PCSK9 is also an acute phase reactant whose expression increases in inflammatory states. The administration of lipopolysaccharide (LPS), an isolated bacterial protein that mimics acute infection or acute systemic inflammation, resulted in a 2.5-fold increase in PCSK9 mRNA levels and an increased PCSK9 expression in kidney tissues in mice.<ref name="Feingold-2008">{{Cite journal | last1 = Feingold | first1 = KR. | last2 = Moser | first2 = AH. | last3 = Shigenaga | first3 = JK. | last4 = Patzek | first4 = SM. | last5 = Grunfeld | first5 = C. | title = Inflammation stimulates the expression of PCSK9. | journal = Biochem Biophys Res Commun | volume = 374 | issue = 2 | pages = 341-4 | month = Sep | year = 2008 | doi = 10.1016/j.bbrc.2008.07.023 | PMID = 18638454 }}</ref> In parallel, previous animal models have shown that LPS administration also produces an approximately 17-fold increase in LDL content of lysolecithin, a product derived from the oxidation of LDL.<ref name="pmid10845869">{{cite journal| author=Memon RA, Staprans I, Noor M, Holleran WM, Uchida Y, Moser AH et al.| title=Infection and inflammation induce LDL oxidation in vivo. | journal=Arterioscler Thromb Vasc Biol | year= 2000 | volume= 20 | issue= 6 | pages= 1536-42 | pmid=10845869 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10845869  }} </ref> These models have also been supported by studies showing strong association between inflammation and atherosclerosis in mice and hamsters.  Although robust clinical data is still lacking, observational studies have shown an increased risk of coronary artery disease in patients with chronic inflammatory disorders.  Furthermore, increased inflammatory markers are associated with adverse outcomes in patients with acute coronary syndromes. <ref name="pmid11877368">{{cite journal| author=Libby P, Ridker PM, Maseri A| title=Inflammation and atherosclerosis. | journal=Circulation | year= 2002 | volume= 105 | issue= 9 | pages= 1135-43 | pmid=11877368 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11877368  }} </ref>


===Apoptosis===
{|
Apoptotic cell death is one of the mechanisms implicated in the development of [[atherosclerosis]]. Oxidized LDL-induced apoptosis of human endothelial cells has been associated with an increased expression of PCSK9.  Pretreatment of human endothelial cells with PCSK9-SiRNA (to inhibit PCSK9 expression) decreased LDL-induced apoptosis by reducing important mediators of apoptosis.  PCSK9 reduced the Bcl-2/Bax ratio and inhibited the activation of both caspase 9 and 3.<ref name="Wu-2012">{{Cite journal | last1 = Wu | first1 = CY. | last2 = Tang | first2 = ZH. | last3 = Jiang | first3 = L. | last4 = Li | first4 = XF. | last5 = Jiang | first5 = ZS. | last6 = Liu | first6 = LS. | title = PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway. | journal = Mol Cell Biochem | volume = 359 | issue = 1-2 | pages = 347-58 | month = Jan | year = 2012 | doi = 10.1007/s11010-011-1028-6 | PMID = 21847580 }}</ref>
|- valign=top
| [[File:PDB 2p4e EBI.png|thumb|'''2p4e''': Crystal structure of PCSK9<ref name="pmid17435765">{{PDB|2P4E}} {{cite journal | vauthors = Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, Varghese AH, Ammirati MJ, Culp JS, Hoth LR, Mansour MN, McGrath KM, Seddon AP, Shenolikar S, Stutzman-Engwall KJ, Warren LC, Xia D, Qiu X | title = Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia | journal = Nat. Struct. Mol. Biol. | volume = 14 | issue = 5 | pages = 413–9 | year = 2007 | pmid = 17435765 | doi = 10.1038/nsmb1235 }}</ref>]]
| [[File:PDB 2pmw EBI.png|thumb|'''2pmw''': Crystal structure of proprotein convertase subtilisin kexin type 9 (PCSK9)<ref name="pmid17502100">{{PDB|2PMW}} {{cite journal | vauthors = Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP | title = The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol | journal = Structure | volume = 15 | issue = 5 | pages = 545–52 | year = 2007 | pmid = 17502100 | doi = 10.1016/j.str.2007.04.004 }}</ref>]]
|}
== Function ==


===Blood Pressure Regulation===
===Role and regulatory function===
The epithelial Na<sup>+</sup> channel (ENaC) regulates sodium homeostasis and plays a regulatory role in blood pressure control.  It is a constitutively active ion-channel in the distal nephron responsible for active sodium reabsorption.  Defects in ENaC are associated with essential forms of hereditary hypertension.  PCSK9 was demonstrated to reduce ENaC protein expression in Xenopus epithelial cells by increasing endoplasmic reticulum-associated degradation and subsequently decreasing apical surface expression.<ref name="Sharotri-2012">{{Cite journal  | last1 = Sharotri | first1 = V. | last2 = Collier | first2 = DM. | last3 = Olson | first3 = DR. | last4 = Zhou | first4 = R. | last5 = Snyder | first5 = PM. | title = Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). | journal = J Biol Chem | volume = 287 | issue = 23 | pages = 19266-74 | month = Jun | year = 2012 | doi = 10.1074/jbc.M112.363382 | PMID = 22493497 }}</ref>


===Glucose Metabolism===
This protein plays a major regulatory role in [[cholesterol]] homeostasis, mainly by reducing LDLR levels on the plasma membrane. Reduced LDLR levels result in decreased metabolism of LDL-particles, which could lead to [[hypercholesterolemia]].<ref name=uendo /> When LDL binds to LDLR, it induces internalization of LDLR-LDL complex within an endosome. The acidity of the endosomal environment induces LDLR to adopt a hairpin conformation.<ref name="Zhang 2007">{{cite journal | vauthors = Zhang DW, et al.| title = Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation | journal = J Biol Chem | date = June 2007 | doi = 10.1074/jbc.M702027200 | volume=282 | pages=18602–18612 | pmid=17452316}}</ref> The conformational change causes LDLR to release its LDL ligand, and the receptor is recycled back to the plasma membrane. However, when PCSK9 binds to the LDLR (through the EGF-A domain), PCSK9 prevents the conformational change of the receptor-ligand complex. This inhibition redirects the LDLR to the lysosome instead.<ref name="Zhang 2007"/>
Both PCSK9 and [[LDL receptor|LDLR]] are expressed in insulin-producing pancreatic islet beta cells, and may be involved in the regulation of blood glucose.  PCSK9-deficient mice were demonstrated to be hypoinsulinemic, hyperglycemic, and glucose-intolerant. Their islet cells exhibited signs of [[malformation]], [[apoptosis]] and [[inflammation]].<ref name="Mbikay-2010">{{Cite journal  | last1 = Mbikay | first1 = M. | last2 = Sirois | first2 = F. | last3 = Mayne | first3 = J. | last4 = Wang | first4 = GS. | last5 = Chen | first5 = A. | last6 = Dewpura | first6 = T. | last7 = Prat | first7 = A. | last8 = Seidah | first8 = NG. | last9 = Chretien | first9 = M. | title = PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. | journal = FEBS Lett | volume = 584 | issue = 4 | pages = 701-6 | month = Feb | year = 2010 | doi = 10.1016/j.febslet.2009.12.018 | PMID = 20026049 }}</ref> Nevertheless, the true effect of PCSK9 inhibition on glucose metabolism is unclear. The inhibition of PCSK9 by monoclonal antibodies had no significant effect on blood glucose and was not associated with worsening glycemic control in patients with diabetes.<ref name="pmid24322554">{{cite journal| author=Mearns BM| title=Dyslipidaemia: 1-Year results from OSLER trial of anti-PCSK9 monoclonal antibody evolocumab. | journal=Nat Rev Cardiol | year= 2014 | volume= 11 | issue= 2 | pages= 63 | pmid=24322554 | doi=10.1038/nrcardio.2013.201 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24322554  }} </ref>


===Adipose Tissue Metabolism===
PCSK9 is synthesized as a soluble [[zymogen]] that undergoes autocatalytic intramolecular processing in the [[endoplasmic reticulum]]. The protein may function as a proprotein convertase.<ref name = "Lagace_2014">{{cite journal | vauthors = Lagace TA | title = PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells | journal = Current Opinion in Lipidology | volume = 25 | issue = 5 | pages = 387–93 | date = October 2014 | pmid = 25110901 | pmc = 4166010 | doi = 10.1097/MOL.0000000000000114 }}</ref> PCSK9 is expressed mainly in the liver, the intestine, the kidney, and the central nervous system.<ref>{{cite journal | vauthors = Norata GD, Tibolla G, Catapano AL | title = Targeting PCSK9 for hypercholesterolemia | journal = Annual Review of Pharmacology and Toxicology | volume = 54 | pages = 273–93 | date = 2014-01-01 | pmid = 24160703 | doi = 10.1146/annurev-pharmtox-011613-140025 }}</ref> PCSK9 also plays an important role in intestinal triglyceride-rich [[Apolipoprotein B|apoB lipoprotein]] production in small intestine and postprandial lipemia.<ref>{{cite journal | vauthors = Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM | title = Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk | journal = Circulation | volume = 132 | issue = 17 | pages = 1648–66 | date = October 2015 | pmid = 26503748 | doi = 10.1161/CIRCULATIONAHA.115.016080 }}</ref><ref>{{cite journal | vauthors = Le May C, Kourimate S, Langhi C, Chétiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P | title = Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 29 | issue = 5 | pages = 684–90 | date = May 2009 | pmid = 19265033 | doi = 10.1161/ATVBAHA.108.181586 }}</ref><ref>{{cite journal | vauthors = Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S | title = Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms | journal = Circulation | volume = 130 | issue = 5 | pages = 431–41 | date = July 2014 | pmid = 25070550 | pmc = 4115295 | doi = 10.1161/CIRCULATIONAHA.113.006720 }}</ref>
PCSK9-deficient mice were demonstrated to have adipocyte hypertrophy, increased in-vivo fatty acid uptake, and in-vitro triglyceride synthesis independent of LDL-receptors. Additionally, there was a 40-fold increase in cell surface levels of very-low-density lipoprotein receptors (VLDLR).<ref name="Roubtsova-2011">{{Cite journal | last1 = Roubtsova | first1 = A. | last2 = Munkonda | first2 = MN. | last3 = Awan | first3 = Z. | last4 = Marcinkiewicz | first4 = J. | last5 = Chamberland | first5 = A. | last6 = Lazure | first6 = C. | last7 = Cianflone | first7 = K. | last8 = Seidah | first8 = NG. | last9 = Prat | first9 = A. | title = Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. | journal = Arterioscler Thromb Vasc Biol | volume = 31 | issue = 4 | pages = 785-91 | month = Apr | year = 2011 | doi = 10.1161/ATVBAHA.110.220988 | PMID = 21273557 }}</ref> However, inhibition of PCSK9 by monoclonal antibodies was not demonstrated to increase central [[obesity]].


==PCSK9 Inhibition==
After being processed in the ER, PCSK9 co-localizes with the protein [[Sortilin 1|sortilin]] on its way through the Golgi and trans-Golgi complex. A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9.<ref>{{cite journal | vauthors = Gustafsen C, Kjolby M, Nyegaard M, Mattheisen M, Lundhede J, Buttenschøn H, Mors O, Bentzon JF, Madsen P, Nykjaer A, Glerup S | title = The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion | journal = Cell Metabolism | volume = 19 | issue = 2 | pages = 310–8 | date = February 2014 | pmid = 24506872 | doi = 10.1016/j.cmet.2013.12.006 }}</ref> In healthy humans, plasma PCSK9 levels directly correlate with plasma sortilin levels, following a [[Circadian rhythm|diurnal rhythm]] similar to cholesterol synthesis.<ref name="ReferenceA">{{cite journal | vauthors = Schulz R, Schlüter KD, Laufs U | title = Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9) | journal = Basic Research in Cardiology | volume = 110 | issue = 2 | page = 4 | date = March 2015 | pmid = 25600226 | pmc = 4298671 | doi = 10.1007/s00395-015-0463-z }}</ref><ref>{{cite journal | vauthors = Cariou B, Langhi C, Le Bras M, Bortolotti M, Lê KA, Theytaz F, Le May C, Guyomarc'h-Delasalle B, Zaïr Y, Kreis R, Boesch C, Krempf M, Tappy L, Costet P | title = Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets | journal = Nutrition & Metabolism | volume = 10 | issue = 1 | page = 4 | date = 2013-01-01 | pmid = 23298392 | pmc = 3548771 | doi = 10.1186/1743-7075-10-4 }}</ref> The plasma PCSK9 concentration is higher in women compared to men, and the PCSK9 concentrations decrease with age in men but increase in women, suggesting that estrogen level most likely plays a role.<ref>{{cite journal | vauthors = Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH | title = Genetic and metabolic determinants of plasma PCSK9 levels | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 7 | pages = 2537–43 | date = July 2009 | pmid = 19351729 | pmc = 2708952 | doi = 10.1210/jc.2009-0141 }}</ref><ref>{{cite journal | vauthors = Baass A, Dubuc G, Tremblay M, Delvin EE, O'Loughlin J, Levy E, Davignon J, Lambert M | title = Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents | journal = Clinical Chemistry | volume = 55 | issue = 9 | pages = 1637–45 | date = September 2009 | pmid = 19628659 | doi = 10.1373/clinchem.2009.126987 }}</ref> PCSK9 gene expression can be regulated by [[Sterol regulatory element-binding protein|sterol-response element binding proteins (SREBP-1/2)]], which also controls LDLR expression.<ref name="ReferenceA"/>
Elevated LDL cholesterol levels in the plasma have previously been associated with the development and progression of [[atherosclerosis]], as well as an increased risk of [[myocardial infarction]] and [[stroke]].  LDL receptors, which are responsible for clearing LDL cholesterol from the circulation, get recycled back into the plasma membrane in order to bind more LDL. A novel approach to the management of dyslipidemia targets the inhibition of the serine protease PCSK9 leading to increased LDL receptor expression and increased LDL cholesterol clearance. <ref name=lopez>{{cite journal | author = Lopez D|title = Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia | journal = Drug News Perspect. | volume = 21|issue = 6 | pages = 323–30 | year = 2008 | pmid = 18836590 | doi = 10.1358/dnp.2008.21.6.1246795 }}</ref><ref name=steinberg>{{cite journal|author = Steinberg D, Witztum JL | title = Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 24 | pages = 9546–7 | year = 2009 | month = June | pmid = 19506257 | pmc = 2701045|doi = 10.1073/pnas.0904560106 }}</ref><ref name=mayer>{{cite journal | author = Mayer G, Poirier S, Seidah NG | title = Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels | journal = J. Biol. Chem. | volume = 283|issue = 46 | pages = 31791–801 | year = 2008 | month = November | pmid = 18799458 | doi = 10.1074/jbc.M805971200 }}</ref><ref name=bms>{{cite web | url = http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi| title = Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease | author = | authorlink = | coauthors = | date = 2008-04-08  | format = | work = Press Release | publisher = FierceBiotech | pages =| language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-18 }}</ref>


===Natural===
PCSK9 may also have a role in the differentiation of cortical neurons.<ref name="Seidah_2003"/>
* ''[[Annexin A2]]'' (AnxA2) is an endogenous compound that binds to the C-terminal domain of PCSK9 thereby preventing the interaction of PCSK9 with the LDL receptors particularly in the extrahepatic tissues. It has been demonstrated to be a functional inhibitor of PCSK9.<ref name="Seidah-2012">{{Cite journal  | last1 = Seidah |first1 = NG. | last2 = Poirier | first2 = S. | last3 = Denis | first3 = M. | last4 = Parker | first4 = R. | last5 = Miao | first5 = B. | last6 = Mapelli |first6 = C. | last7 = Prat | first7 = A. | last8 = Wassef | first8 = H. | last9 = Davignon | first9 = J. | title = Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. | journal = PLoS One | volume = 7 | issue = 7 | pages = e41865 | month =  | year = 2012 | doi = 10.1371/journal.pone.0041865 | PMID = 22848640 }}</ref>
* ''[[Furin]]'' and ''PC5/6A'' are two proprotein convertases that cause proteolytic cleavage of the PCSK9 protein between the R<sub>218</sub> and Q<sub>219</sub> residues resulting in a defective enzyme.  Furin was demonstrated to regulate PCSK9 mRNA levels in hepatocytes.<ref name="pmid21147780">{{cite journal| author=Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C et al.| title=In vivo evidence that furin from hepatocytes inactivates PCSK9. | journal=J Biol Chem | year= 2011 | volume= 286 | issue= 6 | pages= 4257-63 | pmid=21147780 | doi=10.1074/jbc.M110.192104 | pmc=PMC3039354| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21147780  }} </ref>
===Pharmacologic===
Several drugs have been investigated for the inhibition of PCSK9, and have demonstrated a more potent lowering of LDL cholesterol levels than the current available drugs. It is biologically plausible that this reduction in LDL would also lead to a reduction in atherothrombotic events. Initial human trials have demonstrated good tolerability and efficacy in lowering LDL choleterol, but additional phase III clinical trials are ongoing to demonstrate the effect of PCSK9 inhibition on cardiovascular events and outcomes.<ref name=lopez>{{cite journal | author = Lopez D|title = Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia | journal = Drug News Perspect. | volume = 21|issue = 6 | pages = 323–30 | year = 2008 | pmid = 18836590 |doi = 10.1358/dnp.2008.21.6.1246795 }}</ref><ref name=steinberg>{{cite journal|author = Steinberg D, Witztum JL | title = Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 24 | pages = 9546–7 | year = 2009 | month = June | pmid = 19506257 | pmc = 2701045|doi = 10.1073/pnas.0904560106 }}</ref><ref name=mayer>{{cite journal | author = Mayer G, Poirier S, Seidah NG | title = Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels | journal = J. Biol. Chem. | volume = 283|issue = 46 | pages = 31791–801 | year = 2008 | month = November | pmid = 18799458 | doi = 10.1074/jbc.M805971200 }}</ref><ref name=bms>{{cite web | url =http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi| title = Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease | author = | authorlink = | coauthors = |date = 2008-04-08  | format = | work = Press Release | publisher = FierceBiotech | pages =| language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-18 }}</ref>
[[File:Pharmacologic-interventions-for-PCSK9.jpg|800px|center|Pharmacologic-interventions-for-PCSK9]]
<center><font size="1">''Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408''<ref name="Urban-2013">{{Cite journal  | last1 = Urban | first1 = D. | last2 = Pöss | first2 = J. | last3 = Böhm | first3 = M. | last4 = Laufs | first4 = U. | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. | journal = J Am Coll Cardiol | volume = 62 | issue = 16 | pages = 1401-8 | month = Oct | year = 2013 | doi = 10.1016/j.jacc.2013.07.056 | PMID = 23973703 }}</ref></font></center>
====Monoclonal Antibodies====
A number of [[monoclonal antibodies]] that bind to PCSK9 near the catalytic domain that interact with the LDL receptors, and hence inhibit the function of PCSK9 are currently in clinical trials.  These include:
<br>
*'''[[AMG145]]''' or '''[[Evolocumab]]''' by Amgen pharmaceuticals is a human monoclonal IgG2 antibody against PCSK9. Pre-clinical studies, and early clinical trials have shown the efficacy and potency of evolocumab in decreasing LDL cholesterol as an add-on agent or as monotherapy. Further trials are needed to evaluate the efficacy of evolocumab in improving cardiovascular outcomes.<ref name="Raal-2012">{{Cite journal  | last1 = Raal | first1 = F. | last2 = Scott | first2 = R. | last3 = Somaratne | first3 = R. | last4 = Bridges | first4 = I. | last5 = Li | first5 = G. | last6 = Wasserman | first6 = SM. | last7 = Stein | first7 = EA. | title = Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. | journal = Circulation | volume = 126 | issue = 20| pages = 2408-17 | month = Nov | year = 2012 | doi = 10.1161/CIRCULATIONAHA.112.144055 | PMID = 23129602 }}</ref><ref name="Sullivan-2012">{{Cite journal  | last1 = Sullivan| first1 = D. | last2 = Olsson | first2 = AG. | last3 = Scott | first3 = R. | last4 = Kim | first4 = JB. | last5 = Xue | first5 = A. | last6 = Gebski | first6 = V. | last7 = Wasserman | first7 = SM. | last8 = Stein | first8 = EA. | title = Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. | journal = JAMA | volume = 308 | issue = 23 | pages = 2497-506 | month = Dec |year = 2012 | doi = 10.1001/jama.2012.25790 | PMID = 23128163 }}</ref><ref name="pmid23141812">{{cite journal| author=Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L et al.| title=Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. | journal=Lancet | year= 2012 |volume= 380 | issue= 9858 | pages= 1995-2006 | pmid=23141812 | doi=10.1016/S0140-6736(12)61771-1 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23141812  }} </ref><ref name="pmid24322554">{{cite journal| author=Mearns BM| title=Dyslipidaemia: 1-Year results from OSLER trial of anti-PCSK9 monoclonal antibody evolocumab. | journal=Nat Rev Cardiol | year= 2014 | volume= 11 | issue= 2 | pages= 63 | pmid=24322554 | doi=10.1038/nrcardio.2013.201 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24322554  }} </ref><ref name="pmid24825642">{{cite journal| author=Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D et al.| title=Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. | journal=JAMA | year= 2014 | volume= 311 | issue= 18 | pages= 1870-82 | pmid=24825642 | doi=10.1001/jama.2014.4030 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24825642  }} </ref>
*'''SAR236553/REGN727''' or '''Alirocumab''' by Sanofi-Aventis/Regeneron pharmaceuticals<ref name=lambert>{{cite journal | author = Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK | title = The PCSK9 decade | journal = J. Lipid Res. | volume = 53 | issue = 12 | pages = 2515–24 | year = 2012 | month = December | pmid = 22811413 | doi = 10.1194/jlr.R026658 | url = | pmc = 3494258 }}</ref>
:* In a study to determine the safety and efficacy of alirocumab in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy, 183 patients with LDL-C≥100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for≥6 weeks were assigned to subcutaneous injections of alirocumab at 50, 100, or 150 mg doses every 2 weeks, alirocumab 200 or 300 mg every 4 weeks, or placebo every 2 weeks.  After 12 weeks, LDL cholesterol levels were reduced by 40%, 64%, and 72% with 50, 100, and 150 mg in the 2-week-dosing group respectively, and 43% and 48% with 200 and 300 mg in the 4-week-dosing groups respectively. In comparison, patients in the placebo group had a 5% reduction in LDL cholesterol levels.  Alirocumab was also found to reduce non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(A). One case of leukocytoclastic vasculitis was reported.<ref name="pmid22463922">{{cite journal| author=McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA| title=Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. | journal=J Am Coll Cardiol | year= 2012 | volume= 59 | issue= 25 | pages= 2344-53 | pmid=22463922 | doi=10.1016/j.jacc.2012.03.007 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22463922  }} </ref>
:* ''ODYSSEY OUTCOMES'' is a phase III trial designed to evaluate the cardiovascular outcomes after an acute coronary syndrome in patients who have experienced an acute coronary syndrome (ACS) event 4 to 16 weeks prior to enrollment in the study.  This trial is currently ongoing, but not recruiting participants.
*'''RN316''' or '''Bococizumab''' by Pfizer - In a study done by Pfizer to assess the safety and efficacy of RN316, intravenous doses of RN316 was shown to reduce the levels of LDL-C by 46% to 56% in patients already taking high-dose statins.
*'''1D05-IgG2''' by Merck & Co. - This is a PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor thereby reducing LDL cholesterol. It is currently under investigation. <ref name="pmid20959675">{{cite journal| author=Ni YG, Di Marco S, Condra JH, Peterson LB, Wang W, Wang F et al.| title=A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 1 | pages= 78-86 | pmid=20959675 | doi=10.1194/jlr.M011445 | pmc=PMC2999929 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20959675  }} </ref>
<br>
'''Other drugs being evaluated in phase I or II clinical trials include:'''
* '''RG7652''' by Roche/Genentech
* '''LGT-209''' by Novartis
* '''1B20''' by Merck & Co.
* '''J10, J16, J17''' by Pfizer<br>


====Gene Silencing====
=== Clinical significance ===
Several agents work by shutting down the gene responsible for the synthesis of the PCSK9 protein.
* PCSK9 antisense oligonucleotide ('''ISIS 394814''') from Isis Pharmaceuticals has been demonstrated to increase the expression of the LDL receptors and decrease circulating total cholesterol levels in mice.<ref name=graham>{{cite journal | author = Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM |title = Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice| journal = J. Lipid Res. | volume = 48 |issue = 4 | pages = 763–7 | year = 2007 | month = April | pmid = 17242417 | doi = 10.1194/jlr.C600025-JLR200 }}</ref> 
* Locked nucleic acids such as '''SPC4061''' from Santaris Pharma demonstrated reduced PCSK9 mRNA levels when administered in mice.<ref name=gupta>{{cite journal | author = Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM | title = A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo | journal = PLoS ONE | volume = 5 |issue = 5 | pages = e10682 | year = 2010 | pmid = 20498851 | pmc = 2871785 | doi = 10.1371/journal.pone.0010682 | url = | editor1-last = Deb| editor1-first = Sumitra }}</ref><ref name=lindholm>{{cite journal | author = Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T | title = PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates | journal = Mol. Ther. | volume = 20 | issue = 2 | pages = 376–81 | year = 2012 | month = February | pmid = 22108858 |pmc = 3277239 | doi = 10.1038/mt.2011.260 }}</ref>
* '''ALN-PCS''' by The Medicines Company and Alnylam Pharmaceuticals acts by means of [[RNA interference]], which causes the gene to shut down production of the PCSK9 protein.<ref name=alnypharm>{{cite web | url = http://phx.corporate-ir.net/phoenix.zhtml?c=148005&p=irol-newsArticle2&ID=1644329&highlight= | title = Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia | author = | authorlink = | coauthors = | date = 2011-01-04 | format = | work = Press Release | publisher = BusinessWire | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2011-01-04 }}</ref><ref name=frank>{{cite journal | author = Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K | title = Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates| journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 33 | pages = 11915–20 | year = 2008 | month = August | pmid = 18695239 |pmc = 2575310 | doi = 10.1073/pnas.0805434105 }}</ref>  Two drugs are being tested: '''ALN-PCS02''' administered intravenously and '''ALN-PCSsc''' administered subcutaneously.


====Mimetic Peptides====
Variants of PCSK9 can reduce or increase circulating cholesterol. LDL-particles are removed from the blood when they bind to LDLR on the surface of cells, including [[Hepatocyte|liver cells]], and are taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR.<ref name="pmid18753623">{{cite journal | vauthors = Zhang DW, Garuti R, Tang WJ, Cohen JC, Hobbs HH | title = Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 35 | pages = 13045–50 | date = September 2008 | pmid = 18753623 | pmc = 2526098 | doi = 10.1073/pnas.0806312105 | bibcode = 2008PNAS..10513045Z }}</ref> If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove LDL-particles from the bloodstream.<ref name="Pollack_2012" />
PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of LDLR in order to induce its internalization and degradation. A mimetic peptide, which mimics the actions of EGF-A, was demonstrated to competitively inhibit PCSK9-mediated degradation of LDLR in HepG2 cells.<ref name="Shan-2008">{{Cite journal | last1 = Shan | first1 = L. | last2 = Pang | first2 = L. | last3 = Zhang | first3 = R. | last4 = Murgolo | first4 = NJ. | last5 = Lan | first5 = H. | last6 = Hedrick | first6 = JA. | title = PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. | journal = Biochem Biophys Res Commun | volume = 375 | issue = 1 | pages = 69-73 | month = Oct | year = 2008 | doi = 10.1016/j.bbrc.2008.07.106 | PMID = 18675252 }}</ref> Examples of mimetic peptides currently being investigated include:
* '''EGF-AB peptide fragment''' by Schering-Plough
* '''LDLR (H306Y) subfragment''' by U.S. National Institute of Health
* '''LDLR DNA construct''' by U.S. National Institute of Health


====Adnectins====
Other variants are associated with a rare autosomal dominant [[Familial hypercholesterolemia|familial hypercholesterolemia]] (HCHOLA3).<ref name=entrez /><ref name="Abifadel_2003"/><ref name="Dubuc_2004" /> The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.<ref name="Abifadel_2003"/>
Adnectins are genetically engineered target-binding proteins designed bind therapeutic targets.  They are similar to monoclonal antibodies including binding to targets with similar affinity and specificity, but differ in terms of sequence and lack of disulphide bonds in their single-domain structure.<ref name="Lipovsek-2011">{{Cite journal  | last1 = Lipovsek | first1 = D. | title = Adnectins: engineered target-binding protein therapeutics. | journal = Protein Eng Des Sel | volume = 24 | issue = 1-2 | pages = 3-9 | month = Jan | year = 2011 | doi = 10.1093/protein/gzq097 | PMID = 21068165 }}</ref> The adnectin '''BMS-962476''' by Bristol-Myers Squibb/Adnexus has recently completed its phase 1 clinical trial and demonstrated good tolerability with no notable safety signals.


====Small-Molecule Inhibitors====
In humans, PCSK9 was initially discovered as a [[protein]] expressed in the brain.<ref name = "Norata_2016">{{cite journal | vauthors = Norata GD, Tavori H, Pirillo A, Fazio S, Catapano AL | title = Biology of PCSK9: beyond LDL cholesterol lowering | journal = Cardiovascular Research | date = August 2016 | pmid = 27496869 | doi = 10.1093/cvr/cvw194 | volume=112 | pmc=5031950 | pages=429–42}}</ref> However, it has also been described in the kidney, the pancreas, liver and small intestine.<ref name = "Norata_2016"/> Recent evidence indicate that PCSK9 is highly expressed in arterial walls such as [[endothelium]], [[Smooth muscle tissue|smooth muscle]] cells, and [[macrophage]]s, with a local effect that can regulate vascular homeostasis and atherosclerosis.<ref>{{cite journal | vauthors = Ferri N, Tibolla G, Pirillo A, Cipollone F, Mezzetti A, Pacia S, Corsini A, Catapano AL | title = Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels | journal = Atherosclerosis | volume = 220 | issue = 2 | pages = 381–6 | date = February 2012 | pmid = 22176652 | doi = 10.1016/j.atherosclerosis.2011.11.026 }}</ref><ref>{{cite journal | vauthors = Wu CY, Tang ZH, Jiang L, Li XF, Jiang ZS, Liu LS | title = PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway | journal = Molecular and Cellular Biochemistry | volume = 359 | issue = 1–2 | pages = 347–58 | date = January 2012 | pmid = 21847580 | doi = 10.1007/s11010-011-1028-6 }}</ref><ref>{{cite journal | vauthors = Giunzioni I, Tavori H, Covarrubias R, Major AS, Ding L, Zhang Y, DeVay RM, Hong L, Fan D, Predazzi IM, Rashid S, Linton MF, Fazio S | title = Local effects of human PCSK9 on the atherosclerotic lesion | journal = The Journal of Pathology | volume = 238 | issue = 1 | pages = 52–62 | date = January 2016 | pmid = 26333678 | doi = 10.1002/path.4630 | pmc = 5346023 }}</ref> Accordingly, it is now very clear that PCSK9 has pro-atherosclerotic effects and regulates [[lipoprotein]] synthesis.<ref name = "Cohen_2006">{{cite journal | vauthors = Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH | title = Sequence variations in PCSK9, low LDL, and protection against coronary heart disease | journal = The New England Journal of Medicine | volume = 354 | issue = 12 | pages = 1264–72 | date = March 2006 | pmid = 16554528 | doi = 10.1056/NEJMoa054013 }}</ref>
Orally administered small-molecule inhibitors may act by altering the sequence of PCSK9 auto-catalytic intracellular processing, PCSK9 secretion, or LDL receptor interaction.<ref name="Do-2013">{{Cite journal | last1 = Do | first1 = RQ. | last2 = Vogel | first2 = RA. | last3 = Schwartz | first3 = GG. | title = PCSK9 Inhibitors: potential in cardiovascular therapeutics. | journal = Curr Cardiol Rep | volume = 15 | issue = 3 | pages = 345 | month = Mar | year = 2013 | doi = 10.1007/s11886-012-0345-z | PMID = 23338726 }}</ref> It has been also difficult to design a molecule that affects the flat and large target site of PCSK9 for LDL receptors.<ref name="Benjannet-2012">{{Cite journal | last1 = Benjannet | first1 = S. | last2 = Hamelin | first2 = J. | last3 = Chrétien | first3 = M. | last4 = Seidah | first4 = NG. | title = Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. | journal = J Biol Chem | volume = 287 | issue = 40 | pages = 33745-55 | month = Sep | year = 2012 | doi = 10.1074/jbc.M112.399725 | PMID = 22875854 }}</ref> Some small-molecule inhibitors in pre-clinical studies include:
* '''SX-PCK9''' by Serometrix
* '''TBD''' by Shifa Biomedical


==Clinical Significance of PCSK9 Inhibition==
As PCSK9 binds to LDLR, which prevents the removal of [[Ldl cholesterol|LDL-particles]] from the blood plasma, several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).<ref name = "Hlatky_2017"/><ref name = "Norata_2016"/><ref>{{cite journal | vauthors = Groves C, Shetty C, Strange RC, Waldron J, Ramachandran S | title = A study in high-risk, maximally pretreated patients to determine the potential use of PCSK9 inhibitors at various thresholds of total and LDL cholesterol levels | journal = Postgraduate Medical Journal | date = August 2016 | pmid = 27531965 | doi = 10.1136/postgradmedj-2016-134062 | pages=postgradmedj-2016-134062}}</ref><ref>{{cite journal | vauthors = Robinson JG | title = Nonstatins and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Role in Non-Familial Hypercholesterolemia | journal = Progress in Cardiovascular Diseases | date = August 2016 | pmid = 27498088 | doi = 10.1016/j.pcad.2016.07.011 | volume=59 | pages=165–171}}</ref><ref>{{cite journal | vauthors = Rosenson RS, Jacobson TA, Preiss D, Djedjos SC, Dent R, Bridges I, Miller M | title = Erratum to: Efficacy and Safety of the PCSK9 Inhibitor Evolocumab in Patients with Mixed Hyperlipidemia | journal = Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy | date = August 2016 | pmid = 27497929 | doi = 10.1007/s10557-016-6684-z | volume=30 | page=537}}</ref><ref>{{cite journal | vauthors = Peng W, Qiang F, Peng W, Qian Z, Ke Z, Yi L, Jian Z, Chongrong Q | title = Therapeutic efficacy of PCSK9 monoclonal antibodies in statin-nonresponsive patients with hypercholesterolemia and dyslipidemia: A systematic review and meta-analysis | journal = International Journal of Cardiology | volume = 222 | pages = 119–129 | date = July 2016 | pmid = 27494723 | doi = 10.1016/j.ijcard.2016.07.239 }}</ref><ref>{{cite journal | vauthors = Urban D, Pöss J, Böhm M, Laufs U | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis | journal = Journal of the American College of Cardiology | volume = 62 | issue = 16 | pages = 1401–8 | date = October 2013 | pmid = 23973703 | doi = 10.1016/j.jacc.2013.07.056 }}</ref><ref>{{cite journal | vauthors = Norata GD, Tibolla G, Catapano AL | title = PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges | journal = Vascular Pharmacology | volume = 62 | issue = 2 | pages = 103–11 | date = August 2014 | pmid = 24924410 | doi = 10.1016/j.vph.2014.05.011 }}</ref> Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.<ref name = "Cohen_2006"/><ref>{{cite journal | vauthors = Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH | title = Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 | journal = Nature Genetics | volume = 37 | issue = 2 | pages = 161–5 | date = February 2005 | pmid = 15654334 | doi = 10.1038/ng1509 }}</ref><ref>{{cite journal | vauthors = Kathiresan S | title = A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction | journal = The New England Journal of Medicine | volume = 358 | issue = 21 | pages = 2299–300 | date = May 2008 | pmid = 18499582 | doi = 10.1056/NEJMc0707445 }}</ref>
With the discovery of the PCSK9, many preclinical studies and clinical trials have reported the efficacy and safety of PCSK9 inhibition in lowering LDL cholesterol as add on agents or as monotherapy. However, despite the OSLER trial, certain questions regarding the long-term safety are still unanswered.  Monoclonal antibodies against PCSK9 may elicit immunogenicity and immune-mediated responses. This may be reduced with the use of fully human monoclonal antibodies. Further studies are needed to determine the immunogenic effects of these agents and to demonstrate whether or not a risk of antidrug antibodies exists in these patients. <ref name="pmid23817198">{{cite journal| author=Petrides F, Shearston K, Chatelais M, Guilbaud F, Meilhac O, Lambert G| title=The promises of PCSK9 inhibition. | journal=Curr Opin Lipidol | year= 2013 | volume= 24 |issue= 4 | pages= 307-12 | pmid=23817198 | doi=10.1097/MOL.0b013e328361f62d | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23817198}}</ref> Additionally, most PCSK9 inhibitors are administered subcutaneously (few administered intravenously) and they require administration every 2 or 4 weeks raising concerns in regards to ease of use and compliance. Beyond the lowering of LDL cholesterol, the true added value of this class of drugs (PCSK9 inhibitors) can only be determined with large scale phase III trials that evaluate the efficacy of of this approach in the reduction of atherothrombotic events and improving clinical outcomes. Without clear imporvements in outcome measures, this approach to LDL choleterol lowering cannot be adopted.  


The combination of PCSK9 and statins has been of particular interest given the fact that statins have been demonstrated to increase the serum levels of PCSK9, thus affecting their LDL-C lowering capacity.<ref name="Dubuc-2004">{{Cite journal | last1 = Dubuc | first1 = G. | last2 = Chamberland | first2 = A. | last3 = Wassef | first3 = H. | last4 = Davignon | first4 = J. | last5 = Seidah | first5 = NG. | last6 = Bernier | first6 = L. | last7 = Prat | first7 = A. | title = Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. | journal = Arterioscler Thromb Vasc Biol | volume = 24 | issue = 8 | pages = 1454-9 | month = Aug | year = 2004 | doi = 10.1161/01.ATV.0000134621.14315.43 | PMID = 15178557 }}</ref><ref name="Awan-2012">{{Cite journal | last1 = Awan | first1 = Z. | last2 = Seidah | first2 = NG. | last3 = MacFadyen | first3 = JG. | last4 = Benjannet | first4 = S. | last5 = Chasman | first5 = DI. | last6 = Ridker | first6 = PM. | last7 = Genest | first7 = J. | title = Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. | journal = Clin Chem | volume = 58 | issue = 1 | pages = 183-9 | month = Jan | year = 2012 | doi = 10.1373/clinchem.2011.172932 | PMID = 22065156 }}</ref> Subsequently, a statin-PSCK9 inhibitor would theoretically provide a synergistic effect on the reduction of serum levels of LDL cholesterol.
In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in [[Carbohydrate metabolism|glucose metabolism]] and [[obesity]],<ref>{{cite journal | vauthors = Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ | title = Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial | journal = Lancet | volume = 380 | issue = 9841 | pages = 565–71 | date = August 2012 | pmid = 22883507 | pmc = 3774022 | doi = 10.1016/S0140-6736(12)61190-8 }}</ref> regulation of re-absorption of sodium in the kidney which is relevant in hypertension.<ref>{{cite journal | vauthors = Berger JM, Vaillant N, Le May C, Calderon C, Brégeon J, Prieur X, Hadchouel J, Loirand G, Cariou B | title = PCSK9-deficiency does not alter blood pressure and sodium balance in mouse models of hypertension | journal = Atherosclerosis | volume = 239 | issue = 1 | pages = 252–9 | date = March 2015 | pmid = 25621930 | doi = 10.1016/j.atherosclerosis.2015.01.012 }}</ref><ref>{{cite journal | vauthors = Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM | title = Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9) | journal = The Journal of Biological Chemistry | volume = 287 | issue = 23 | pages = 19266–74 | date = June 2012 | pmid = 22493497 | pmc = 3365958 | doi = 10.1074/jbc.M112.363382 }}</ref> Furthermore, PCSK9 may be involved in bacterial or viral infections and sepsis.<ref>{{cite journal | vauthors = Norata GD, Pirillo A, Ammirati E, Catapano AL | title = Emerging role of high density lipoproteins as a player in the immune system | journal = Atherosclerosis | volume = 220 | issue = 1 | pages = 11–21 | date = January 2012 | pmid = 21783193 | doi = 10.1016/j.atherosclerosis.2011.06.045 }}</ref><ref>{{cite journal | vauthors = Diedrich G | title = How does hepatitis C virus enter cells? | journal = The FEBS Journal | volume = 273 | issue = 17 | pages = 3871–85 | date = September 2006 | pmid = 16934030 | doi = 10.1111/j.1742-4658.2006.05379.x }}</ref> In the brain the role of PCSK9 is still controversial and may be either pro-[[Apoptosis|apoptotic]] or protective in the development of the nervous system.<ref name = "Seidah_2003"/> PCSK9 levels have been detected in the [[cerebrospinal fluid]] at a 50-60 times lower level than in serum.<ref>{{cite journal | vauthors = Chen YQ, Troutt JS, Konrad RJ | title = PCSK9 is present in human cerebrospinal fluid and is maintained at remarkably constant concentrations throughout the course of the day | journal = Lipids | volume = 49 | issue = 5 | pages = 445–55 | date = May 2014 | pmid = 24659111 | doi = 10.1007/s11745-014-3895-6 }}</ref>


==References==
=== Clinical marker ===
{{Reflist|2}}
A multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).<ref name="Mega_2015" />


{{Lipopedia}}
== PCSK9 Inhibitor Drugs ==
[[Category:Lipopedia]]
Several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called [[hypercholesterolemia]]).<ref name = "Hlatky_2017"/><ref name = "Norata_2016"/> Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.<ref name = "Cohen_2006"/>


{{WikiDoc Help Menu}}
PCSK9 inhibitor drugs are now approved by the [[Food and Drug Administration|FDA]] to treat familial hypercholesterolemia.<ref name="NYT2018" />
{{WikiDoc Sources}}
 
=== As a drug target === <!-- target for PCSK9 inhibitor -->
 
Drugs can inhibit PCSK9, leading to lowered circulating LDL particle concentrations. Since LDL particle concentrations are thought by many experts to be a driver of [[cardiovascular disease]] like [[Myocardial infarction|heart attack]]s, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including [[Phases of clinical research|phase III clinical trials]], are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs.<ref name="Lopez_2008" /><ref name="Steinberg_2009" /><ref name="Mayer_2008" /><ref name=bms /><ref name="FitzgeraldWhite2017" /> Among those inhibitors under development in December 2013 were the antibodies [[alirocumab]], [[evolocumab]], 1D05-IgG2 ([[Merck & Co.|Merck]]), RG-7652 and LY3015014, as well as the [[RNAi]] therapeutic [[inclisiran]].<ref name=sheridan2013>{{cite journal | vauthors = Sheridan C | title = Phase 3 data for PCSK9 inhibitor wows | journal = Nature Biotechnology | volume = 31 | issue = 12 | pages = 1057–8 | date = December 2013 | pmid = 24316621 | doi = 10.1038/nbt1213-1057 }}</ref> PCSK9 inhibitors are promising therapeutics for the treatment of people who exhibit statin intolerance, or as a way to bypass frequent dosage of statins for higher LDL concentration reduction.<ref name="pmid25432394">{{cite journal | vauthors = Stein EA, Raal FJ | title = New therapies for reducing low-density lipoprotein cholesterol | journal = Endocrinology and Metabolism Clinics of North America | volume = 43 | issue = 4 | pages = 1007–33 | date = December 2014 | pmid = 25432394 | doi = 10.1016/j.ecl.2014.08.008 }}</ref><ref name="pmid22465426">{{cite journal | vauthors = Vogel RA | title = PCSK9 inhibition: the next statin? | journal = Journal of the American College of Cardiology | volume = 59 | issue = 25 | pages = 2354–5 | date = June 2012 | pmid = 22465426 | doi = 10.1016/j.jacc.2012.03.011 }}</ref>
 
A review published in 2015 concluded that these agents, when used in patients with high LDL-particle concentrations (thus at greatly elevated risk for cardiovascular disease) seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and [[Myocardial infarction|heart attack]]s.<ref name="pmid25915661">{{cite journal | vauthors = Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D'Agostino RB, Kubica J, Volpe M, Agewall S, Kereiakes DJ, Kelm M | title = Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis | journal = Annals of Internal Medicine | volume = 163 | issue = 1 | pages = 40–51 | date = July 2015 | pmid = 25915661 | doi = 10.7326/M14-2957 }}</ref> However more recent reviews conclude that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals,<ref name="pmid28639183">{{cite journal | vauthors = Durairaj A, Sabates A, Nieves J, Moraes B, Baum S | title = Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data | journal = Current Treatment Options in Cardiovascular Medicine | volume = 19 | issue = 8 | pages = 58 | date = August 2017 | pmid = 28639183 | doi = 10.1007/s11936-017-0556-0 }}</ref> PCSK9 inhibitor use probably results in little or no difference in mortality.<ref name="pmid28453187">{{cite journal | vauthors = Schmidt AF, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP | title = PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = | pages = CD011748 | date = April 2017 | pmid = 28453187 | doi = 10.1002/14651858.CD011748.pub2 }}</ref>
 
[[Regeneron]] (in collaboration with [[Sanofi]]) became the first to market a PCSK9 inhibitor, with a competitor [[Amgen]] reaching market slightly later.<ref name="NYT2018" />  The drugs are approved by the FDA for treatment of hypercholesterolemia, notably the genetic condition heterozygous [[familial hypercholesterolemia]] which causes high cholesterol levels and heart attacks at a young age.
 
====Warning====
An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their [[Phase III]] clinical trials.<ref>{{cite web | first = John | last = Carroll | name-list-format = vanc | work = FierceBiotech | date = 7 March 2014 | url = http://www.fiercebiotech.com/story/regeneron-sanofi-and-amgen-shares-suffer-fdas-frets-about-pcsk9-drug/2014-03-07 | title = Regeneron, Sanofi and Amgen shares suffer on FDA's frets about PCSK9 class }}</ref>
 
=== Monoclonal antibodies ===
 
A number of [[monoclonal antibodies]] that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials {{as of|2014|lc=y}}. These include [[evolocumab]] ([[Amgen]]), [[bococizumab]] ([[Pfizer]]), and [[alirocumab]] ([[Aventis]]/[[Regeneron]]).<ref name="Lambert_2012" /> {{as of|2015|7}}, the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. A [[meta-analysis]] of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.<ref name="pmid25915661"/>
 
A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.<ref name="pmid24094767">{{cite journal | vauthors = Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J, Nochur SV, Kotelianski V, Horton J, Mant T, Chiesa J, Ritter J, Munisamy M, Vaishnaw AK, Gollob JA, Simon A | title = Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial | journal = Lancet | volume = 383 | issue = 9911 | pages = 60–8 | date = January 2014 | pmid = 24094767 | pmc = 4387547 | doi = 10.1016/S0140-6736(13)61914-5 }}</ref>
 
=== Peptide mimics ===
 
Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.<ref name="Shan_2008" />
 
=== Gene silencing ===
 
The PCSK9 [[antisense oligonucleotide]] increases expression of the LDLR and decreases circulating total cholesterol levels in mice.<ref name="Graham_2007" /> A locked nucleic acid reduced PCSK9 [[mRNA]] levels in mice.<ref name="Gupta_2010" /><ref name="Lindholm_2012" /> Initial clinical trials showed positive results of ALN-PCS, which acts by means of [[RNA interference]].<ref name="FitzgeraldWhite2017" /><ref name=alnypharm /><ref name="Frank-Kamenetsky_2008" />
 
=== Vaccination ===
 
A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP ([[virus-like particle]]) as an immunogenic carrier of an antigenic PCSK9 peptide. VLP's are viruses that have had their DNA removed so that they retain their external structure for antigen display but are unable to replicate; they can induce an immune response without causing infection. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer [[IgG]] [[antibodies]] that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.<ref name="Crosse_2015">{{cite journal | vauthors = Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT | title = A cholesterol-lowering VLP vaccine that targets PCSK9 | journal = Vaccine | volume = 33 | issue = 43 | pages = 5747–55 | date = October 2015 | pmid = 26413878 | doi = 10.1016/j.vaccine.2015.09.044 | pmc=4609631}}</ref>
 
=== Naturally occurring inhibitors ===
 
The plant alkaloid [[berberine]] inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes ''in vitro,''<ref name="Li_2009" /> and lowers serum PCSK9 in mice and hamsters ''in vivo''.<ref name="Dong_2015">{{cite journal | vauthors = Dong B, Li H, Singh AB, Cao A, Liu J | title = Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway | journal = The Journal of Biological Chemistry | volume = 290 | issue = 7 | pages = 4047–58 | date = February 2015 | pmid = 25540198 | pmc = 4326815 | doi = 10.1074/jbc.M114.597229 }}</ref> It has been speculated<ref name="Dong_2015" /> that this action contributes to the ability of berberine to lower serum cholesterol.<ref>{{cite journal | vauthors = Dong H, Zhao Y, Zhao L, Lu F | title = The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials | journal = Planta Medica | volume = 79 | issue = 6 | pages = 437–46 | date = April 2013 | pmid = 23512497 | doi = 10.1055/s-0032-1328321 }}</ref> [[Annexin A2]], an endogenous protein, is a natural inhibitor of PCSK9 activity.<ref name="Seidah_2012" />
 
== References ==
{{reflist|33em|refs=
 
<ref name="Abifadel_2003">{{cite journal | vauthors = Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C | title = Mutations in PCSK9 cause autosomal dominant hypercholesterolemia | journal = Nat. Genet. | volume = 34 | issue = 2 | pages = 154–6 |date=June 2003 | pmid = 12730697 | doi = 10.1038/ng1161 }}</ref>
 
<ref name=alnypharm>{{cite web | url = http://phx.corporate-ir.net/phoenix.zhtml?c=148005&p=irol-newsArticle2&ID=1644329&highlight= | title = Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia | date = 2011-01-04 | work = Press Release | publisher = BusinessWire | pages = | archiveurl =https://archive.is/20130221150726/http://phx.corporate-ir.net/phoenix.zhtml?c=148005&p=irol-newsArticle2&ID=1644329&highlight=| archivedate =2013-02-21| quote = | dead-url = yes | accessdate = 2011-01-04 }}</ref>
 
<ref name=bms>{{cite web | url = http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi | title = Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease | date = 2008-04-08 | work = Press Release | publisher = FierceBiotech | pages = | quote = | accessdate = 2010-09-18 }}</ref>
 
<ref name="Dubuc_2004">{{cite journal | vauthors = Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A | title = Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 24 | issue = 8 | pages = 1454–9 |date=August 2004 | pmid = 15178557 | doi = 10.1161/01.ATV.0000134621.14315.43 }}</ref>
 
<ref name=entrez>{{cite web | title = Entrez Gene: PCSK9 proprotein convertase subtilisin/kexin type 9| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=255738| accessdate = }}</ref>
 
<ref name="Frank-Kamenetsky_2008">{{cite journal | vauthors = Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K | title = Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 33 | pages = 11915–20 | date = August 2008 | pmid = 18695239 | pmc = 2575310 | doi = 10.1073/pnas.0805434105 | bibcode = 2008PNAS..10511915F }}</ref>
 
<ref name="Graham_2007">{{cite journal | vauthors = Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM | title = Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice | journal = J. Lipid Res. | volume = 48 | issue = 4 | pages = 763–7 |date=April 2007 | pmid = 17242417 | doi = 10.1194/jlr.C600025-JLR200 }}</ref>
 
<ref name="Gupta_2010">{{cite journal | vauthors = Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM | title = A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo | journal = PLoS ONE | volume = 5 | issue = 5 | pages = e10682 | year = 2010 | pmid = 20498851 | pmc = 2871785 | doi = 10.1371/journal.pone.0010682 | url = | editor1-last = Deb | editor1-first = Sumitra | bibcode = 2010PLoSO...510682G }}</ref>
 
<!-- <ref name=kolata>{{cite news | url = https://www.nytimes.com/2013/07/10/health/rare-mutation-prompts-race-for-cholesterol-drug.html | title = Rare Mutation Ignites Race for Cholesterol Drug | author = Kolata G | date = July 9, 2013 | work = The New York Times }}</ref> -->
 
<ref name="Lambert_2012">{{cite journal | vauthors = Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK | title = The PCSK9 decade | journal = J. Lipid Res. | volume = 53 | issue = 12 | pages = 2515–24 |date=December 2012 | pmid = 22811413 | doi = 10.1194/jlr.R026658 | pmc = 3494258 }}</ref>
 
<ref name="Lindholm_2012">{{cite journal | vauthors = Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T | title = PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates | journal = Mol. Ther. | volume = 20 | issue = 2 | pages = 376–81 |date=February 2012 | pmid = 22108858 | pmc = 3277239 | doi = 10.1038/mt.2011.260 }}</ref>
 
<ref name="Lopez_2008">{{cite journal | vauthors = Lopez D | title = Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia | journal = Drug News Perspect. | volume = 21 | issue = 6 | pages = 323–30 | year = 2008 | pmid = 18836590 | doi = 10.1358/dnp.2008.21.6.1246795 }}</ref>
 
<ref name="Mayer_2008">{{cite journal | vauthors = Mayer G, Poirier S, Seidah NG | title = Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels | journal = J. Biol. Chem. | volume = 283 | issue = 46 | pages = 31791–801 | date = November 2008 | pmid = 18799458 | doi = 10.1074/jbc.M805971200 }}</ref>
 
<ref name="Pollack_2012">{{cite news | url = https://www.nytimes.com/2012/11/06/business/new-drugs-for-lipids-set-off-race.html | title = New Drugs for Lipids Set Off Race | vauthors = Pollack A | date = 5 November 2012 | work = [[The New York Times]] }}</ref>
 
<ref name = "Seidah_2003">{{cite journal | vauthors = Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 3 | pages = 928–33 |date=February 2003 | pmid = 12552133 | pmc = 298703 | doi = 10.1073/pnas.0335507100 | bibcode = 2003PNAS..100..928S }}</ref>
 
<ref name="Shan_2008">{{cite journal | vauthors = Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA | title = PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide | journal = Biochem. Biophys. Res. Commun. | volume = 375 | issue = 1 | pages = 69–73 | date = October 2008 | pmid = 18675252 | doi = 10.1016/j.bbrc.2008.07.106 }}</ref>
 
<ref name="Steinberg_2009">{{cite journal | vauthors = Steinberg D, Witztum JL | title = Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 24 | pages = 9546–7 |date=June 2009 | pmid = 19506257 | pmc = 2701045 | doi = 10.1073/pnas.0904560106 | bibcode = 2009PNAS..106.9546S }}</ref>
 
<ref name=uendo>{{cite web | url = http://www.uendocrine.com/resources/presentations/item/36-the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol | title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol | accessdate = 13 May 2015 | deadurl = yes | archiveurl = https://web.archive.org/web/20150518100734/http://www.uendocrine.com/resources/presentations/item/36-the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol | archivedate = 18 May 2015 | df =  }}</ref>
 
<ref name="Li_2009">{{cite journal | vauthors = Li H, Dong B, Park SW, Lee HS, Chen W, Liu J | title = HNF1α plays a critical role in PCSK9 gene transcription and regulation by a natural hypocholesterolemic compound berberine | journal = The Journal of Biological Chemistry | volume = 284 | issue = 42 | pages = 28885–95 | date = August 2009 | pmid = 19687008 | pmc = 2781434 | doi = 10.1074/jbc.M109.052407 }}</ref>
 
<ref name="Seidah_2012">{{cite journal | vauthors = Seidah NG, Poirier S, Denis M, Parker R, Miao B, Mapelli C, Prat A, Wassef H, Davignon J, Hajjar KA, Mayer G | title = Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation | journal = PLoS ONE | volume = 7 | issue = 7 | pages = e41865 | year = 2012 | pmid = 22848640 | pmc = 3407131 | doi = 10.1371/journal.pone.0041865 | bibcode = 2012PLoSO...741865S }}</ref>
 
<!-- <ref name = Zhang_Eigenbrot>{{cite journal | vauthors = Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W, Quan C, Tom J, Moran P, Di Lello P, Skelton NJ, Kong-Beltran M, Peterson A, Kirchhofer D | title = Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor | journal = J. Biol. Chem. | volume = 289 | issue = 2 | pages = 942–55 | year = 2014 | pmid = 24225950 | pmc = 3887217 | doi = 10.1074/jbc.M113.514067 | url = }}</ref> -->
 
<ref name="FitzgeraldWhite2017">{{cite journal | last1=Fitzgerald | first1=Kevin | last2=White | first2=Suellen | last3=Borodovsky | first3=Anna | last4=Bettencourt | first4=Brian R. | last5=Strahs | first5=Andrew | last6=Clausen | first6=Valerie | last7=Wijngaard | first7=Peter | last8=Horton | first8=Jay D. | last9=Taubel | first9=Jorg | last10=Brooks | first10=Ashley | last11=Fernando | first11=Chamikara | last12=Kauffman | first12=Robert S. | last13=Kallend | first13=David | last14=Vaishnaw | first14=Akshay | last15=Simon | first15=Amy | title=A Highly Durable RNAi Therapeutic Inhibitor of PCSK9 | journal=New England Journal of Medicine | volume=376 | issue=1 | year=2017 | pages=41–51 | issn=0028-4793 | doi=10.1056/NEJMoa1609243 | pmid=27959715 }}</ref>
 
}}
 
== Further reading ==
{{refbegin|33em}}
<!-- alphabetised on author1last -->
* {{cite journal | vauthors = Abifadel M, Rabès JP, Boileau C, Varret M | title = [After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9] | language = French | journal = Ann. Endocrinol. |location = Paris | volume = 68 | issue = 2–3 | pages = 138–46 | date = June 2007 | pmid = 17391637 | doi = 10.1016/j.ando.2007.02.002 }}
* {{cite journal | vauthors = Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabès JP | title = Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia | journal = Hum. Mutat. | volume = 26 | issue = 5 | page = 497 | date = November 2005 | pmid = 16211558 | doi = 10.1002/humu.9383 }}
* {{cite journal | vauthors = Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chrétien M, Prat A, Seidah NG | title = NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol | journal = J. Biol. Chem. | volume = 279 | issue = 47 | pages = 48865–75 | date = November 2004 | pmid = 15358785 | doi = 10.1074/jbc.M409699200 }}
* {{cite journal | vauthors = Lalanne F, Lambert G, Amar MJ, Chétiveaux M, Zaïr Y, Jarnoux AL, Ouguerram K, Friburg J, Seidah NG, Brewer HB, Krempf M, Costet P | title = Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells | journal = J. Lipid Res. | volume = 46 | issue = 6 | pages = 1312–9 | date = June 2005 | pmid = 15741654 | doi = 10.1194/jlr.M400396-JLR200 }}
* {{cite journal | vauthors = Lambert G | title = Unravelling the functional significance of PCSK9 | journal = Curr. Opin. Lipidol. | volume = 18 | issue = 3 | pages = 304–9 | date = June 2007 | pmid = 17495605 | doi = 10.1097/MOL.0b013e3281338531 }}
* {{cite journal | vauthors = Leren TP | title = Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia | journal = Clin. Genet. | volume = 65 | issue = 5 | pages = 419–22 | date = May 2004 | pmid = 15099351 | doi = 10.1111/j.0009-9163.2004.0238.x }}
* {{cite journal | vauthors = Maxwell KN, Breslow JL | title = Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 18 | pages = 7100–5 | date = May 2004 | pmid = 15118091 | pmc = 406472 | doi = 10.1073/pnas.0402133101 | bibcode = 2004PNAS..101.7100M }}
* {{cite journal | vauthors = Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL | title = Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice | journal = J. Lipid Res. | volume = 44 | issue = 11 | pages = 2109–19 | date = November 2003 | pmid = 12897189 | doi = 10.1194/jlr.M300203-JLR200 }}
* {{cite journal | vauthors = Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK | title = Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 25 | issue = 12 | pages = 2654–60 | date = December 2005 | pmid = 16224054 | doi = 10.1161/01.ATV.0000190668.94752.ab }}
* {{cite journal | vauthors = Naureckiene S, Ma L, Sreekumar K, Purandare U, Lo CF, Huang Y, Chiang LW, Grenier JM, Ozenberger BA, Jacobsen JS, Kennedy JD, DiStefano PS, Wood A, Bingham B | title = Functional characterization of Narc 1, a novel proteinase related to proteinase K | journal = Arch. Biochem. Biophys. | volume = 420 | issue = 1 | pages = 55–67 | date = December 2003 | pmid = 14622975 | doi = 10.1016/j.abb.2003.09.011 }}
* {{cite journal | vauthors = Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M | title = Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9 | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 24 | issue = 8 | pages = 1448–53 | date = August 2004 | pmid = 15166014 | doi = 10.1161/01.ATV.0000133684.77013.88 }}
* {{cite journal | vauthors = Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, Cantafora A, Patel D, Averna M, Tarugi P, Calandra S, Bertolini S | title = Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia | journal = Atherosclerosis | volume = 186 | issue = 2 | pages = 433–40 | date = June 2006 | pmid = 16183066 | doi = 10.1016/j.atherosclerosis.2005.08.015 }}
* {{cite journal | vauthors = Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, Watanabe T, Kawashima R, Kitajima A, Ueki A, Nagao M, Arai H | title = No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients | journal = Psychiatr. Genet. | volume = 15 | issue = 4 | page = 239 | date = December 2005 | pmid = 16314752 | doi = 10.1097/00041444-200512000-00004 }}
* {{cite journal | vauthors = Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK | title = Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia | journal = Hum. Mol. Genet. | volume = 14 | issue = 9 | pages = 1161–9 | date = May 2005 | pmid = 15772090 | doi = 10.1093/hmg/ddi128 }}
* {{cite journal | vauthors = Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM | title = A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree | journal = Hum. Genet. | volume = 114 | issue = 4 | pages = 349–53 | date = March 2004 | pmid = 14727179 | doi = 10.1007/s00439-003-1071-9 }}
* {{cite journal | vauthors = Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, Devillers M, Krempf M, Coulon M, Thiart R, Kotze MJ, Schmidt H, Buzzi JC, Kostner GM, Bertolini S, Pocovi M, Rosa A, Farnier M, Martinez M, Junien C, Boileau C | title = A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32 | journal = Am. J. Hum. Genet. | volume = 64 | issue = 5 | pages = 1378–87 | date = May 1999 | pmid = 10205269 | pmc = 1377874 | doi = 10.1086/302370 }}
{{refend}}

Latest revision as of 14:09, 29 October 2018

Not to be confused with PKCS#9.
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Orthologs
SpeciesHumanMouse
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1.[1] It is the 9th member of the proprotein convertase family of proteins that activate other proteins.[2] Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme.[3] The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[4]

PCSK9 is ubiquitously expressed in many tissues and cell types.[5] PCSK9 binds to the receptor for low-density lipoprotein particles (LDL), which typically transport 3,000 to 6,000 fat molecules (including cholesterol) per particle, within extracellular fluid. The LDL receptor (LDLR), on liver and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells, thus reducing LDL particle concentrations. If PCSK9 is blocked, more LDLRs are recycled and are present on the surface of cells to remove LDL-particles from the extracellular fluid.[6] Therefore, blocking PCSK9 can lower blood LDL-particle concentrations.[7][8]

PCSK9 has medical importance because it acts in lipoprotein homeostasis. Agents which block PCSK9 can lower LDL particle concentrations. The first two PCSK9 inhibitors, alirocumab and evolocumab, were approved as once every two week injections, by the U.S. Food and Drug Administration in 2015 for lowering LDL-particle concentrations when statins and other drugs were not sufficiently effective or poorly tolerated. The cost of these new medications, as of 2015, was $14,000 per year at full retail; judged of unclear cost effectiveness by some.[9] While these medications are prescribed by many physicians, the payment for prescriptions are often denied by insurance providers.[10][11][12]

History

In February 2003, Nabil Seidah, a scientist at the Clinical Research Institute of Montreal in Canada, discovered a novel human proprotein convertase, the gene for which was located on the short arm of chromosome 1.[13] Meanwhile, a lab led by Catherine Boileau at the Necker-Enfants Malades Hospital in Paris had been following families with familial hypercholesterolaemia, a genetic condition that, in 90% of cases causes coronary artery disease (FRAMINGHAM study) and in 60% of cases may lead to an early death;[14] they had identified a mutation on chromosome 1 carried by some of these families, but had been unable to identify the relevant gene. The labs got together and by the end of the year published their work, linking mutations in the gene, now identified as PCSK9, to the condition.[15][13] In their paper, they speculated that the mutations might make the gene overactive. In that same year, investigators at Rockefeller University and University of Texas Southwestern had discovered the same protein in mice, and had worked out the novel pathway that regulates LDL cholesterol in which PCSK9 is involved, and it soon became clear that the mutations identified in France led to excessive PCSK9 activity, and thus excessive removal of the LDL receptor, leaving people carrying the mutations with too much LDL cholesterol.[13] Meanwhile, Dr. Helen H. Hobbs and Dr. Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples.[16] With the new knowledge about the role of PCSK9 and its location in the genome, they sequenced the relevant region of chromosome 1 in people with very low cholesterol and they found nonsense mutations in the gene, thus validating PCSK9 as a biological target for drug discovery.[13][17]

In July 2015, the FDA approved the first PCSK9 Inhibitor drugs for medical use.[18]

Structure

Gene

The PCSK9 gene resides on chromosome 1 at the band 1p32.3[19] and includes 13 exons.[20] This gene produces two isoforms through alternative splicing.[21]

Protein

PCSK9 is a member of the peptidase S8 family.[21]

The solved structure of PCSK9 reveals four major components in the pre-processed protein: the signal peptide (residues 1-30); the N-terminal prodomain (residues 31-152); the catalytic domain (residues 153-425); and the C-terminal domain (residues 426-692), which is further divided into three modules.[22] The N-terminal prodomain has a flexible crystal structure and is responsible for regulating PCSK9 function by interacting with and blocking the catalytic domain, which otherwise binds the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR.[22][23][24] While previous studies indicated that the C-terminal domain was uninvolved in binding LDLR,[25][26] a recent study by Du et al. demonstrated that the C-terminal domain does bind LDLR.[22] The secretion of PCSK9 is largely dependent on the autocleavage of the signal peptide and N-terminal prodomain, though the N-terminal prodomain retains its association with the catalytic domain. In particular, residues 61-70 in the N-terminal prodomain are crucial for its autoprocessing.[22]

File:PDB 2p4e EBI.png
2p4e: Crystal structure of PCSK9[27]
File:PDB 2pmw EBI.png
2pmw: Crystal structure of proprotein convertase subtilisin kexin type 9 (PCSK9)[28]

Function

Role and regulatory function

This protein plays a major regulatory role in cholesterol homeostasis, mainly by reducing LDLR levels on the plasma membrane. Reduced LDLR levels result in decreased metabolism of LDL-particles, which could lead to hypercholesterolemia.[29] When LDL binds to LDLR, it induces internalization of LDLR-LDL complex within an endosome. The acidity of the endosomal environment induces LDLR to adopt a hairpin conformation.[30] The conformational change causes LDLR to release its LDL ligand, and the receptor is recycled back to the plasma membrane. However, when PCSK9 binds to the LDLR (through the EGF-A domain), PCSK9 prevents the conformational change of the receptor-ligand complex. This inhibition redirects the LDLR to the lysosome instead.[30]

PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase.[3] PCSK9 is expressed mainly in the liver, the intestine, the kidney, and the central nervous system.[31] PCSK9 also plays an important role in intestinal triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia.[32][33][34]

After being processed in the ER, PCSK9 co-localizes with the protein sortilin on its way through the Golgi and trans-Golgi complex. A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9.[35] In healthy humans, plasma PCSK9 levels directly correlate with plasma sortilin levels, following a diurnal rhythm similar to cholesterol synthesis.[36][37] The plasma PCSK9 concentration is higher in women compared to men, and the PCSK9 concentrations decrease with age in men but increase in women, suggesting that estrogen level most likely plays a role.[38][39] PCSK9 gene expression can be regulated by sterol-response element binding proteins (SREBP-1/2), which also controls LDLR expression.[36]

PCSK9 may also have a role in the differentiation of cortical neurons.[1]

Clinical significance

Variants of PCSK9 can reduce or increase circulating cholesterol. LDL-particles are removed from the blood when they bind to LDLR on the surface of cells, including liver cells, and are taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR.[40] If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove LDL-particles from the bloodstream.[41]

Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3).[42][15][43] The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.[15]

In humans, PCSK9 was initially discovered as a protein expressed in the brain.[44] However, it has also been described in the kidney, the pancreas, liver and small intestine.[44] Recent evidence indicate that PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis.[45][46][47] Accordingly, it is now very clear that PCSK9 has pro-atherosclerotic effects and regulates lipoprotein synthesis.[48]

As PCSK9 binds to LDLR, which prevents the removal of LDL-particles from the blood plasma, several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).[9][44][49][50][51][52][53][54] Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.[48][55][56]

In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in glucose metabolism and obesity,[57] regulation of re-absorption of sodium in the kidney which is relevant in hypertension.[58][59] Furthermore, PCSK9 may be involved in bacterial or viral infections and sepsis.[60][61] In the brain the role of PCSK9 is still controversial and may be either pro-apoptotic or protective in the development of the nervous system.[1] PCSK9 levels have been detected in the cerebrospinal fluid at a 50-60 times lower level than in serum.[62]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[4]

PCSK9 Inhibitor Drugs

Several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).[9][44] Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.[48]

PCSK9 inhibitor drugs are now approved by the FDA to treat familial hypercholesterolemia.[10]

As a drug target

Drugs can inhibit PCSK9, leading to lowered circulating LDL particle concentrations. Since LDL particle concentrations are thought by many experts to be a driver of cardiovascular disease like heart attacks, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including phase III clinical trials, are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs.[63][64][65][66][67] Among those inhibitors under development in December 2013 were the antibodies alirocumab, evolocumab, 1D05-IgG2 (Merck), RG-7652 and LY3015014, as well as the RNAi therapeutic inclisiran.[68] PCSK9 inhibitors are promising therapeutics for the treatment of people who exhibit statin intolerance, or as a way to bypass frequent dosage of statins for higher LDL concentration reduction.[69][70]

A review published in 2015 concluded that these agents, when used in patients with high LDL-particle concentrations (thus at greatly elevated risk for cardiovascular disease) seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and heart attacks.[71] However more recent reviews conclude that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals,[72] PCSK9 inhibitor use probably results in little or no difference in mortality.[73]

Regeneron (in collaboration with Sanofi) became the first to market a PCSK9 inhibitor, with a competitor Amgen reaching market slightly later.[10] The drugs are approved by the FDA for treatment of hypercholesterolemia, notably the genetic condition heterozygous familial hypercholesterolemia which causes high cholesterol levels and heart attacks at a young age.

Warning

An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their Phase III clinical trials.[74]

Monoclonal antibodies

A number of monoclonal antibodies that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials as of 2014. These include evolocumab (Amgen), bococizumab (Pfizer), and alirocumab (Aventis/Regeneron).[75] As of July 2015, the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. A meta-analysis of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.[71]

A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.[76]

Peptide mimics

Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[77]

Gene silencing

The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice.[78] A locked nucleic acid reduced PCSK9 mRNA levels in mice.[79][80] Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.[67][81][82]

Vaccination

A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP (virus-like particle) as an immunogenic carrier of an antigenic PCSK9 peptide. VLP's are viruses that have had their DNA removed so that they retain their external structure for antigen display but are unable to replicate; they can induce an immune response without causing infection. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.[83]

Naturally occurring inhibitors

The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro,[84] and lowers serum PCSK9 in mice and hamsters in vivo.[85] It has been speculated[85] that this action contributes to the ability of berberine to lower serum cholesterol.[86] Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity.[87]

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  64. ↑ Steinberg D, Witztum JL (June 2009). "Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels". Proc. Natl. Acad. Sci. U.S.A. 106 (24): 9546–7. Bibcode:2009PNAS..106.9546S. doi:10.1073/pnas.0904560106. PMC 2701045. PMID 19506257.
  65. ↑ Mayer G, Poirier S, Seidah NG (November 2008). "Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels". J. Biol. Chem. 283 (46): 31791–801. doi:10.1074/jbc.M805971200. PMID 18799458.
  66. ↑ "Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease". Press Release. FierceBiotech. 2008-04-08. Retrieved 2010-09-18.
  67. ↑ 67.0 67.1 Fitzgerald, Kevin; White, Suellen; Borodovsky, Anna; Bettencourt, Brian R.; Strahs, Andrew; Clausen, Valerie; Wijngaard, Peter; Horton, Jay D.; Taubel, Jorg; Brooks, Ashley; Fernando, Chamikara; Kauffman, Robert S.; Kallend, David; Vaishnaw, Akshay; Simon, Amy (2017). "A Highly Durable RNAi Therapeutic Inhibitor of PCSK9". New England Journal of Medicine. 376 (1): 41–51. doi:10.1056/NEJMoa1609243. ISSN 0028-4793. PMID 27959715.
  68. ↑ Sheridan C (December 2013). "Phase 3 data for PCSK9 inhibitor wows". Nature Biotechnology. 31 (12): 1057–8. doi:10.1038/nbt1213-1057. PMID 24316621.
  69. ↑ Stein EA, Raal FJ (December 2014). "New therapies for reducing low-density lipoprotein cholesterol". Endocrinology and Metabolism Clinics of North America. 43 (4): 1007–33. doi:10.1016/j.ecl.2014.08.008. PMID 25432394.
  70. ↑ Vogel RA (June 2012). "PCSK9 inhibition: the next statin?". Journal of the American College of Cardiology. 59 (25): 2354–5. doi:10.1016/j.jacc.2012.03.011. PMID 22465426.
  71. ↑ 71.0 71.1 Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D'Agostino RB, Kubica J, Volpe M, Agewall S, Kereiakes DJ, Kelm M (July 2015). "Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis". Annals of Internal Medicine. 163 (1): 40–51. doi:10.7326/M14-2957. PMID 25915661.
  72. ↑ Durairaj A, Sabates A, Nieves J, Moraes B, Baum S (August 2017). "Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data". Current Treatment Options in Cardiovascular Medicine. 19 (8): 58. doi:10.1007/s11936-017-0556-0. PMID 28639183.
  73. ↑ Schmidt AF, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP (April 2017). "PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease". The Cochrane Database of Systematic Reviews. 4: CD011748. doi:10.1002/14651858.CD011748.pub2. PMID 28453187.
  74. ↑ Carroll J (7 March 2014). "Regeneron, Sanofi and Amgen shares suffer on FDA's frets about PCSK9 class". FierceBiotech.
  75. ↑ Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK (December 2012). "The PCSK9 decade". J. Lipid Res. 53 (12): 2515–24. doi:10.1194/jlr.R026658. PMC 3494258. PMID 22811413.
  76. ↑ Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J, Nochur SV, Kotelianski V, Horton J, Mant T, Chiesa J, Ritter J, Munisamy M, Vaishnaw AK, Gollob JA, Simon A (January 2014). "Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial". Lancet. 383 (9911): 60–8. doi:10.1016/S0140-6736(13)61914-5. PMC 4387547. PMID 24094767.
  77. ↑ Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA (October 2008). "PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide". Biochem. Biophys. Res. Commun. 375 (1): 69–73. doi:10.1016/j.bbrc.2008.07.106. PMID 18675252.
  78. ↑ Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM (April 2007). "Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice". J. Lipid Res. 48 (4): 763–7. doi:10.1194/jlr.C600025-JLR200. PMID 17242417.
  79. ↑ Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM (2010). Deb S, ed. "A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo". PLoS ONE. 5 (5): e10682. Bibcode:2010PLoSO...510682G. doi:10.1371/journal.pone.0010682. PMC 2871785. PMID 20498851.
  80. ↑ Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T (February 2012). "PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates". Mol. Ther. 20 (2): 376–81. doi:10.1038/mt.2011.260. PMC 3277239. PMID 22108858.
  81. ↑ "Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia". Press Release. BusinessWire. 2011-01-04. Archived from the original on 2013-02-21. Retrieved 2011-01-04.
  82. ↑ Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K (August 2008). "Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates". Proc. Natl. Acad. Sci. U.S.A. 105 (33): 11915–20. Bibcode:2008PNAS..10511915F. doi:10.1073/pnas.0805434105. PMC 2575310. PMID 18695239.
  83. ↑ Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT (October 2015). "A cholesterol-lowering VLP vaccine that targets PCSK9". Vaccine. 33 (43): 5747–55. doi:10.1016/j.vaccine.2015.09.044. PMC 4609631. PMID 26413878.
  84. ↑ Li H, Dong B, Park SW, Lee HS, Chen W, Liu J (August 2009). "HNF1α plays a critical role in PCSK9 gene transcription and regulation by a natural hypocholesterolemic compound berberine". The Journal of Biological Chemistry. 284 (42): 28885–95. doi:10.1074/jbc.M109.052407. PMC 2781434. PMID 19687008.
  85. ↑ 85.0 85.1 Dong B, Li H, Singh AB, Cao A, Liu J (February 2015). "Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway". The Journal of Biological Chemistry. 290 (7): 4047–58. doi:10.1074/jbc.M114.597229. PMC 4326815. PMID 25540198.
  86. ↑ Dong H, Zhao Y, Zhao L, Lu F (April 2013). "The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials". Planta Medica. 79 (6): 437–46. doi:10.1055/s-0032-1328321. PMID 23512497.
  87. ↑ Seidah NG, Poirier S, Denis M, Parker R, Miao B, Mapelli C, Prat A, Wassef H, Davignon J, Hajjar KA, Mayer G (2012). "Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation". PLoS ONE. 7 (7): e41865. Bibcode:2012PLoSO...741865S. doi:10.1371/journal.pone.0041865. PMC 3407131. PMID 22848640.

Further reading

  • Abifadel M, Rabès JP, Boileau C, Varret M (June 2007). "[After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9]". Ann. Endocrinol. (in French). Paris. 68 (2–3): 138–46. doi:10.1016/j.ando.2007.02.002. PMID 17391637.
  • Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabès JP (November 2005). "Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia". Hum. Mutat. 26 (5): 497. doi:10.1002/humu.9383. PMID 16211558.
  • Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chrétien M, Prat A, Seidah NG (November 2004). "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol". J. Biol. Chem. 279 (47): 48865–75. doi:10.1074/jbc.M409699200. PMID 15358785.
  • Lalanne F, Lambert G, Amar MJ, Chétiveaux M, Zaïr Y, Jarnoux AL, Ouguerram K, Friburg J, Seidah NG, Brewer HB, Krempf M, Costet P (June 2005). "Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells". J. Lipid Res. 46 (6): 1312–9. doi:10.1194/jlr.M400396-JLR200. PMID 15741654.
  • Lambert G (June 2007). "Unravelling the functional significance of PCSK9". Curr. Opin. Lipidol. 18 (3): 304–9. doi:10.1097/MOL.0b013e3281338531. PMID 17495605.
  • Leren TP (May 2004). "Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia". Clin. Genet. 65 (5): 419–22. doi:10.1111/j.0009-9163.2004.0238.x. PMID 15099351.
  • Maxwell KN, Breslow JL (May 2004). "Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype". Proc. Natl. Acad. Sci. U.S.A. 101 (18): 7100–5. Bibcode:2004PNAS..101.7100M. doi:10.1073/pnas.0402133101. PMC 406472. PMID 15118091.
  • Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (November 2003). "Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice". J. Lipid Res. 44 (11): 2109–19. doi:10.1194/jlr.M300203-JLR200. PMID 12897189.
  • Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK (December 2005). "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response". Arterioscler. Thromb. Vasc. Biol. 25 (12): 2654–60. doi:10.1161/01.ATV.0000190668.94752.ab. PMID 16224054.
  • Naureckiene S, Ma L, Sreekumar K, Purandare U, Lo CF, Huang Y, Chiang LW, Grenier JM, Ozenberger BA, Jacobsen JS, Kennedy JD, DiStefano PS, Wood A, Bingham B (December 2003). "Functional characterization of Narc 1, a novel proteinase related to proteinase K". Arch. Biochem. Biophys. 420 (1): 55–67. doi:10.1016/j.abb.2003.09.011. PMID 14622975.
  • Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M (August 2004). "Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1448–53. doi:10.1161/01.ATV.0000133684.77013.88. PMID 15166014.
  • Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, Cantafora A, Patel D, Averna M, Tarugi P, Calandra S, Bertolini S (June 2006). "Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia". Atherosclerosis. 186 (2): 433–40. doi:10.1016/j.atherosclerosis.2005.08.015. PMID 16183066.
  • Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, Watanabe T, Kawashima R, Kitajima A, Ueki A, Nagao M, Arai H (December 2005). "No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients". Psychiatr. Genet. 15 (4): 239. doi:10.1097/00041444-200512000-00004. PMID 16314752.
  • Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK (May 2005). "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia". Hum. Mol. Genet. 14 (9): 1161–9. doi:10.1093/hmg/ddi128. PMID 15772090.
  • Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM (March 2004). "A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree". Hum. Genet. 114 (4): 349–53. doi:10.1007/s00439-003-1071-9. PMID 14727179.
  • Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, Devillers M, Krempf M, Coulon M, Thiart R, Kotze MJ, Schmidt H, Buzzi JC, Kostner GM, Bertolini S, Pocovi M, Rosa A, Farnier M, Martinez M, Junien C, Boileau C (May 1999). "A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32". Am. J. Hum. Genet. 64 (5): 1378–87. doi:10.1086/302370. PMC 1377874. PMID 10205269.
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