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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
One member of this family has garnered intense interest as a clinical drug target. As liver PCSK9 acts to maintain cholesterol homeostasis, it has become a target of intense interest for clinical drug development. Inhibition of PCSK9 can lower low-density cholesterol (LDL-C) by clearing LDLR-bound LDL particles, thereby lowering circulating cholesterol levels. It is hypothesised that this action may improve outcomes in patients with atherosclerotic cardiovascular disease [4-6]. Therapeutics which inhibit PCSK9 are viewed as potentially lucrative replacements for statins, upon statin patent expiry. Several monoclonal antibodies including alirocumab, evolocumab, bococizumab, RG-7652 and LY3015014 are under development. One RNAi therapeutic, code named ALN-PCS02, is also in development [1-3].
1. Cully M. (2013) Dyslipidaemia: RNAi targeting PCSK9 decreases lipid levels in a human trial. Nat Rev Cardiol, 10 (12): 682. [PMID:24145894]
2. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J et al.. (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. [PMID:24094767]
3. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y et al.. (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. [PMID:18695239]
4. Lopez D. (2008) Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia. Drug News Perspect., 21 (6): 323-30. [PMID:18836590]
5. Sahebkar A, Chew GT, Watts GF. (2014) Recent advances in pharmacotherapy for hypertriglyceridemia. Prog. Lipid Res., 56C: 47-66 [Epub ahead of print]. [PMID:25083925]
6. 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. [PMID:19506257]
Database page citation:
S8: Subtilisin. Accessed on 24/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=755.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol. 172: 6024-6109.