Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro

Chem Biol. 2014 Feb 20;21(2):284-94. doi: 10.1016/j.chembiol.2013.11.014. Epub 2014 Jan 16.

Abstract

Disrupting the binding interaction between proprotein convertase (PCSK9) and the epidermal growth factor-like domain A (EGF-A domain) in the low-density lipoprotein receptor (LDL-R) is a promising strategy to promote LDL-R recycling and thereby lower circulating cholesterol levels. In this study, truncated 26 amino acid EGF-A analogs were designed and synthesized, and their structures were analyzed in solution and in complex with PCSK9. The most potent peptide had an increased binding affinity for PCSK9 (KD = 0.6 μM) compared with wild-type EGF-A (KD = 1.2 μM), and the ability to increase LDL-R recycling in the presence of PCSK9 in a cell-based assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Line
  • Cholesterol / metabolism
  • Epidermal Growth Factor / chemistry
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutagenesis
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / metabolism*
  • Proprotein Convertase 9
  • Proprotein Convertases / chemistry
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, LDL / metabolism*
  • Serine Endopeptidases / chemistry
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*

Substances

  • Peptides
  • Receptors, LDL
  • Epidermal Growth Factor
  • Cholesterol
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases