The identification of the
HMG-CoA reductase inhibitors,
statins, has represented a dramatic innovation of the pharmacological modulation of
hypercholesterolemia and associated
cardiovascular diseases. However, not all patients receiving
statins achieve guideline-recommended
low density lipoprotein (
LDL) cholesterol goals, particularly those at high risk. There remains, therefore, an unmet medical need to develop additional well-tolerated and effective agents to lower
LDL cholesterol levels. The discovery of
proprotein convertase subtilisin/kexin type 9 (PCSK9), a secretory
protein that posttranscriptionally regulates levels of
low density lipoprotein receptor (LDLR) by inducing its degradation, has opened a new era of pharmacological modulation of
cholesterol homeostasis. This paper summarizes the current knowledge of the basic molecular mechanism underlying the regulatory effect of LDLR expression by PCSK9 obtained from in vitro cell-cultured studies and the analysis of the crystal structure of PCSK9. It also describes the epidemiological and experimental evidences of the regulatory effect of PCSK9 on
LDL cholesterol levels and
cardiovascular diseases and summarizes the different pharmacological approaches under development for inhibiting PCSK9 expression, processing, and the interaction with LDLR.