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

Department of Internal Medicine, Division of Translational Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9185, USA.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 07/2008; 16(12):6338-43. DOI: 10.1016/j.bmc.2008.05.015
Source: PubMed


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.

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    • "Only five of the approximately 300,000 beads screened (approximately 0.0017% of the population) were observed to bind PAE/KDR (redstained ) cells alone (Fig. 2) indicating those bound through VEGFR2. In subsequent validation experiments, we found that all five of these peptoids bind to a single 'hot spot' on the VEGFR2 surface (Udugamasooriya et al., 2008c). We have dimerized one of those compounds to display strong anti-angiogeic properties both in vitro and in vivo mice models (Astle, 2008; Lynn et al., 2010; Roland et al., 2009; Udugamasooriya et al., 2008a; Udugamasooriya et al., 2008b) as well as attached Gd(III) based contrast agents to image VEGF receptors at the cellular level and in vivo mice models using MRI (De Leon- Rodriguez et al., 2010). "
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