Homotrimerization Approach in the Design of Thrombospondin-1 Mimetic Peptides with Improved Potency in Triggering Regulated Cell Death of Cancer Cells

J Med Chem. 2019 Sep 12;62(17):7656-7668. doi: 10.1021/acs.jmedchem.9b00024. Epub 2019 Aug 26.

Abstract

In order to optimize the potency of the first serum-stable peptide agonist of CD47 (PKHB1) in triggering regulated cell death of cancer cells, we designed a maturation process aimed to mimic the trimeric structure of the thrombospondin-1/CD47 binding epitope. For that purpose, an N-methylation scan of the PKHB1 sequence was realized to prevent peptide aggregation. Structural and pharmacological analyses were conducted in order to assess the conformational impact of these chemical modifications on the backbone structure and the biological activity. This structure-activity relationship study led to the discovery of a highly soluble N-methylated peptide that we termed PKT16. Afterward, this monomer was used for the design of a homotrimeric peptide mimic that we termed [PKT16]3, which proved to be 10-fold more potent than its monomeric counterpart. A pharmacological evaluation of [PKT16]3 in inducing cell death of adherent (A549) and nonadherent (MEC-1) cancer cell lines was also performed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Protein Conformation
  • Protein Stability
  • Structure-Activity Relationship
  • Thrombospondin 1 / chemistry*
  • Thrombospondin 1 / pharmacology

Substances

  • Peptides
  • Thrombospondin 1
  • thrombospondin-1, human