Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment

J Med Chem. 2022 Dec 8;65(23):15513-15539. doi: 10.1021/acs.jmedchem.2c01290. Epub 2022 Nov 29.


The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD. In this review, we have discussed the role of PCSK9 in lipid metabolism and briefly summarized the current clinical status of modalities targeting PCSK9. In particular, a detailed overview of peptide-based PCSK9 inhibitors is presented, which emphasizes their structural features and design, therapeutic effects on patients, and preclinical cardiovascular disease (CVD) models, along with PCSK9 modulation mechanisms. As a promising alternative to monoclonal antibodies (mAbs) for managing LDL-C, anti-PCSK9 peptides are emerging as a prospective next generation therapy.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cholesterol, LDL / chemistry
  • Cholesterol, LDL / metabolism
  • Humans
  • Hypercholesterolemia* / drug therapy
  • PCSK9 Inhibitors* / chemistry
  • PCSK9 Inhibitors* / pharmacology
  • Proprotein Convertase 9 / drug effects


  • Cholesterol, LDL
  • PCSK9 Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9