Proprotein convertase subtilisin/kexin type 9 inhibition.
OBJECTIVE
There are now ample data that demonstrate that inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) can safely lower LDL cholesterol synergistically with statins. Considering that PCSK9 was first identified less than a decade ago, the last few years have shown rapid and remarkable advancements in our understanding and knowledge of the structure and function of PCSK9.


RESULTS
Therapeutic developments have not lagged far behind with some monoclonal antibodies currently entering phase III trials. Of the many approaches to PCSK9 inhibition, these compounds are the furthest advanced in their clinical development while small molecule oral inhibitors seem a distant prospect.


CONCLUSIONS
This review summarizes the discovery and history of PCSK9 and in particular its mode of action as an inhibitor of the LDL receptor. It also recapitulates key studies that have demonstrated the potential of inhibiting PCSK9 to further decrease LDL-cholesterol levels safely and synergistically with statins. Finally, we review the strategies that are currently in development to inhibit PCSK9, with a special emphasis on the spectacular results from recent phase-I and phase-II clinical trials.
Department of Chemical Pathology bDepartment of Medicine, University of Cape Town, Cape Town, South Africa.
David A
DA
Marais
Dirk J
DJ
Blom
Francine
F
Petrides
Yann
Y
Gouëffic
Gilles
G
Lambert
D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008247:Lysosomes / Q000201:enzymology; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018832:Molecular Chaperones; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases