Proprotein convertase subtilisin/kexin type 9: from the discovery to the development of new therapies for cardiovascular diseases

Abstract

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.

Figure 1

Schematic representation of the PCSK9-mediated LDLR degradation process. (a) On the cell surface at neutral pH, the LDLR can adopt an open extended conformation and binds to LDL predominantly through the L4 and L5 domains of the LDL repeats. At low endosomal pH, LDLR adopts the closed form releasing the LDL and allowing its recycle to the cell surface. (b) Circulating PCSK9 binds the LDLR, restraining its flexibility at the EFG-B-βpropeller interface. The low pH of the endosomes enhances PCSK9/LDLR affinity, preventing complex dissociation and conformational changes leading to lysosomal LDLR degradation. A possible interaction of the PCSK9 C-terminal domain (CTD) at the endosomal pH has also been described to strengthen the binding between the two proteins.