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

21 Citations (Scopus)

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

Fingerprint

Peptoids
Vascular Endothelial Growth Factor Receptor
Binding Sites
Vascular Endothelial Growth Factor A
Hormones
Macular Degeneration
Conformations
Immunoglobulins
Tumors
Peptides
Neoplasms

Keywords

  • Peptoid
  • Protein-ligand binding
  • VEGF receptor

ASJC Scopus subject areas

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

Cite this

A peptoid antagonist of VEGF Receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site. / Udugamasooriya, D. Gomika; Ritchie, Caroline; Brekken, Rolf A.; Kodadek, Thomas.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 12, 15.06.2008, p. 6338-6343.

Research output: Contribution to journalArticle

@article{cd2113d97f554d41b55d44ab412f85e4,
title = "A peptoid antagonist of VEGF Receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site",
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.",
keywords = "Peptoid, Protein-ligand binding, VEGF receptor",
author = "Udugamasooriya, {D. Gomika} and Caroline Ritchie and Brekken, {Rolf A.} and Thomas Kodadek",
year = "2008",
month = "6",
day = "15",
doi = "10.1016/j.bmc.2008.05.015",
language = "English (US)",
volume = "16",
pages = "6338--6343",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "12",

}

TY - JOUR

T1 - A peptoid antagonist of VEGF Receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site

AU - Udugamasooriya, D. Gomika

AU - Ritchie, Caroline

AU - Brekken, Rolf A.

AU - Kodadek, Thomas

PY - 2008/6/15

Y1 - 2008/6/15

N2 - 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.

AB - 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.

KW - Peptoid

KW - Protein-ligand binding

KW - VEGF receptor

UR - http://www.scopus.com/inward/record.url?scp=44649199913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44649199913&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2008.05.015

DO - 10.1016/j.bmc.2008.05.015

M3 - Article

C2 - 18501615

AN - SCOPUS:44649199913

VL - 16

SP - 6338

EP - 6343

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 12

ER -