PCSK9 inhibition
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]
Overview
Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme that in humans is encoded by the PCSK9 gene.[1] Similar genes (orthologs) are found across many species. Many enzymes are inactive when they are first synthesized, because they have a section of peptide chains that blocks their activity. Proprotein convertases remove that section to activate the enzyme. PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.[2]
Function
This 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.
This protein plays a major regulatory role in cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of low-density lipoproteins (LDL), which could lead to hypercholesterolemia.[3] 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 cholesterol is removed from the blood when it binds to LDL receptors on the surface of liver cells, and is taken inside the cells. When PCSK9 binds to the LDL receptor, the receptor is destroyed along with the LDL. But if PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol.[2]
Some variants, which only reduce cholesterol by 15% in whites, are associated with a reduction in coronary heart disease by 50%.
Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3).[4][5][6] The mutations increase its protease activity, reducing LDL receptor levels and preventing the uptake of cholesterol into the cells.[5]
As a drug target
Drugs can inhibit PCSK9, and lower cholesterol much more than available drugs. It is biologically plausible that this would also lower heart attacks and other diseases caused by raised cholesterol. Studies with humans, including phase III clinical trials are now underway to find out whether PCSK9 inhibition actually does lower disease, with acceptable side effects.[7][8][9][10]
Monoclonal antibodies
A number of monoclonal antibodies that bind to PCSK9 near the catalytic domain that interact with the LDLR and hence inhibit the function of PCSK9 are currently in clinical trials. These include AMG145 (Amgen), 1D05-IgG2 (Merck & Co.), and SAR236553/REGN727 (Aventis/Regeneron).[11]
Peptide mimics
Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[12]
Gene silencing
PCSK9 antisense oligonucleotide from Isis Pharmaceuticals has been shown to increase expression of the LDLR and decrease circulating total cholesterol levels in mice.[13] A locked nucleic acid from Santaris Pharma reduced PCSK9 mRNA levels in mice.[14][15]
Alnylam Pharmaceuticals has shown in initial clinical trials positive results of ALN-PCS which acts by means of RNA interference, as an effective means of PCSK9 inhibition.[16][17]
Structure
References
- ↑ 1.0 1.1 Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation". Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMC 298703. PMID 12552133. Unknown parameter
|month=ignored (help) - ↑ 2.0 2.1 Pollack A (November 5, 2012). "New Drugs for Lipids Set Off Race". New York Times.
- ↑ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". 2012-11-11.
- ↑ "Entrez Gene: PCSK9 proprotein convertase subtilisin/kexin type 9".
- ↑ 5.0 5.1 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 (2003). "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia". Nat. Genet. 34 (2): 154–6. doi:10.1038/ng1161. PMID 12730697. Unknown parameter
|month=ignored (help) - ↑ Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (2004). "Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1454–9. doi:10.1161/01.ATV.0000134621.14315.43. PMID 15178557. Unknown parameter
|month=ignored (help) - ↑ Lopez D (2008). "Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia". Drug News Perspect. 21 (6): 323–30. doi:10.1358/dnp.2008.21.6.1246795. PMID 18836590.
- ↑ Steinberg D, Witztum JL (2009). "Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels". Proc. Natl. Acad. Sci. U.S.A. 106 (24): 9546–7. doi:10.1073/pnas.0904560106. PMC 2701045. PMID 19506257. Unknown parameter
|month=ignored (help) - ↑ Mayer G, Poirier S, Seidah NG (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. Unknown parameter
|month=ignored (help) - ↑ "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.
- ↑ Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK (2012). "The PCSK9 decade". J. Lipid Res. 53 (12): 2515–24. doi:10.1194/jlr.R026658. PMC 3494258. PMID 22811413. Unknown parameter
|month=ignored (help) - ↑
- ↑ Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM (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. Unknown parameter
|month=ignored (help) - ↑ Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM (2010). Deb, Sumitra, ed. "A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo". PLoS ONE. 5 (5): e10682. doi:10.1371/journal.pone.0010682. PMC 2871785. PMID 20498851.
- ↑ Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T (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. Unknown parameter
|month=ignored (help) - ↑ "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. Retrieved 2011-01-04.
- ↑ 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 (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. doi:10.1073/pnas.0805434105. PMC 2575310. PMID 18695239. Unknown parameter
|month=ignored (help)