A Peptoid “Antibody Surrogate” That Antagonizes VEGF Receptor 2 Activity

Division of Translational Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9185, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 05/2008; 130(17):5744-52. DOI: 10.1021/ja711193x
Source: PubMed


We report a two-color, cell-based screen to identify specific receptor-binding compounds in a combinatorial library of peptoids displayed on beads. We apply this strategy to the isolation of vascular endothelial growth factor receptor 2 (VEGFR2)-binding peptoids. A dimeric derivative of one of these lead compounds is shown to be an antagonist of VEGFR2 activity both in vitro and in vivo. This methodology provides a potentially general route to synthetic molecules that bind integral membrane receptors with affinities and specificities similar to those of antibodies, but which are far smaller and easier to make and manipulate.

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Available from: Gomika Udugamasooriya,
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    • "Structural studies (Herbert et al., 2013) suggest that the small molecule attains its selectivity by targeting an extracellular domain that is present only in the D2D3 region of FGF receptor (Fig. 7B). In addition to this small molecule example, there is evidence that the extracellular domains of RTKs can be allosterically targeted by peptide-mimetics, "peptoids," and antibodies (Fleishman et al., 2002; Udugamasooriya et al., 2008; Cazorla et al., 2010; Jura et al., 2011). 5. Antibody Modulation of Receptor Tyrosine Kinase Activity. The recent upsurge in interest in monoclonal antibodies that target RTKs and their associated signaling pathways is uncovering new mechanisms of allostery that involve different interaction domains on the receptor and even the cognate ligand. "
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    • "In order to substantially increase the number of compounds that could be used in such a screen, we first developed a protocol that allowed one-bead, one-compound (OBOC) libraries synthesized on hydrophilic TentaGel beads to be used directly in the screening step. Libraries of hundreds of thousands, or even millions, of peptoids are easily prepared in this format by splitand-pool solid-phase synthesis (Alluri et al., 2003; Figliozzi et al., 1996; Lam et al., 1991), and these libraries can be used productively in screening experiments using recombinant proteins (Lim et al., 2007; Xiao et al., 2007) or cells (Lau et al., 2002; Mikawa et al., 2004; Udugamasooriya et al., 2008) as targets. The strategy that we envisioned is shown in Figure 1A. "
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