Targeting PCSK9 for the treatment of hypercholesterolemia.
PCSK9 (proprotein convertase subtilisin/kexin type 9) mediates the post-translational degradation of the LDL receptor (LDLR) and, as a result, modulates serum levels of LDL-cholesterol (LDL-C). Individuals with gain-of-function mutations in the PCSK9 gene exhibit high serum levels of LDL-C, while those with loss-of-function mutations have low serum levels of LDL-C and are protected from heart disease. Similarly, mice lacking the expression of PCSK9 exhibit higher levels of LDLR in the liver and reduced serum cholesterol, while the overexpression of PCSK9 reduces LDLR and results in increased serum cholesterol. Thus, as a novel, validated target for controlling serum levels of LDL-C, PCSK9 has attracted research attention. The biological inhibition of PCSK9 appears feasible, and preclinical programs based on RNAi targeting of the protein are at an advanced stage. In contrast, the development of conventional small-molecule therapeutics to inhibit PCSK9 continues to present challenges.
Hedrick
Joseph A
JA
Schering-Plough Research Institute, Department of Cardiovascular and Metabolic Disease Research, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. joseph.hedrick@spcorp.com
D000818:Animals; D020134:Catalytic Domain; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D008078:Cholesterol, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases