Potent Lys Patch-Containing Stapled Peptides Targeting PCSK9

J Med Chem. 2021 Aug 12;64(15):10834-10848. doi: 10.1021/acs.jmedchem.0c02051. Epub 2021 Jul 15.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), identified as a regulator of low-density lipoprotein receptor (LDLR), plays a major role in cardiovascular diseases (CVD). Recently, Pep2-8, a small peptide with discrete three-dimensional structure, was found to inhibit the PCSK9/LDLR interaction. In this paper, we describe the modification of this peptide using stapled peptide and SIP technologies. Their combination yielded potent compounds such as 18 that potently inhibited the binding of PCSK9 to LDLR (KD = 6 ± 1 nM) and restored in vitro LDL uptake by HepG2 cells in the presence of PCSK9 (EC50 = 175 ± 40 nM). The three-dimensional structures of key peptides were extensively studied by circular dichroism and nuclear magnetic resonance, and molecular dynamics simulations allowed us to compare their binding mode to tentatively rationalize structure-activity relationships (SAR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Hep G2 Cells
  • Humans
  • Lysine / chemistry
  • Lysine / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • PCSK9 Inhibitors*
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Proprotein Convertase 9 / metabolism
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • PCSK9 Inhibitors
  • Peptides
  • Serine Proteinase Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Lysine