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

Abstract

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.

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

“…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).…”

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

“…Similarly, agents targeting the extracellular domains of RTKs act outside the kinase domain (Christopoulos et al, 2014). The extracellular domains of RTKs can be targeted by peptide mimetics, peptoids, or antibodies (Fleishman et al, 2002;Udugamasooriya et al, 2008;Cazorla et al, 2010;Jura et al, 2011). The monoclonal antibodies trastuzumab (Herceptin) and pertuzumab (2C4, Perjeta) act at different domains, with trastuzumab binding to domain IV and pertuzumab binding to subdomain II of the extracellular segments of the HER2/neu receptor, respectively (Cho et al, 2003;Hynes and Lane, 2005;Hsieh and Moasser, 2007).…”

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

“…The first anchor ligand was identified by screening a comprehensive one-bead-one-compound (OBOC) peptide library consisting of short chain peptides, against fluorescently labelled bCA-II. 147,148 Analysis of the position-dependent frequency of amino acids identified the anchor ligand, a short heptapeptide comprised of non-natural Damino acids and a terminal, acetylene-containing amino acid D-propargylglycine (D-Pra), showing an approximately 500 μM affinity for bCA-II. This anchor ligand was used in the second screen against the OBOC peptide library, in which peptides were modified with an azide linker, in the presence of bCA-II to identify the triazole product showing a 3 μM binding affinity for bCA-II.…”