A peptoid antagonist of VEGF Receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site

D. Gomika Udugamasooriya, Caroline Ritchie, Rolf A. Brekken, Thomas Kodadek

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Antagonists of VEGF-mediated angiogenesis are of great interest clinically for the treatment of solid tumors and certain forms of macular degeneration. We recently described a novel peptoid antagonist of VEGF Receptor 2 (VEGFR2) that binds to the extracellular domain of the receptor and inhibits VEGF-mediated autophosphorylation and subsequent downstream signaling. Given the structural similarities between peptides and peptoids, an obvious model for the mode of action of the peptoid is that it competes with VEGF for binding to VEGFR2. However, we present evidence here that this is not the case and that VEGF and the peptoid antagonist recognize non-overlapping surfaces located within the first three immunoglobulin-like subdomains of the receptor. These data argue that the peptoid inhibits receptor-mediated autophosphorylation by a novel allosteric mechanism that may prevent the receptor from acquiring the conformation necessary to propagate downstream signals.

Original languageEnglish (US)
Pages (from-to)6338-6343
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number12
DOIs
StatePublished - Jun 15 2008

Keywords

  • Peptoid
  • Protein-ligand binding
  • VEGF receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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