Sulfono-γ-AApeptides recently developed in our group have been proven to be a new class of unnatural foldamer with well-defined helical structure and have been demonstrated to mimic protein helical domains and disrupt biomedically relevant protein-protein interactions (PPIs). Based on our design concept in a recent report, we discovered two similar sulfono-γ-AApeptides V2 and V3 which were designed to mimic the VEGF N-terminal helix α1 known to directly interact with VEGFRs. Interestingly, V2 was shown to possess the pro-angiogenic effect, whereas V3 was proved to be a potent inhibitor for angiogenesis. We speculate that the distinct angiogenesis signaling was due to the selective binding of the two molecules to VEGFR1 and VEGFR2, respectively. Together with their remarkable resistance to proteolytic degradation, relatively small sizes, and amenability to modification with diverse functional groups, V2 and V3 could serve as lead molecules for the development of potential therapeutic agents and molecular probes. These findings highlight sulfono-γ-AApeptides as an alternative paradigm to mimic the α-helical domain to modulate a wide variety of PPIs in the future.
Keywords: VEGF; VEGFR; angiogenesis; modulators; peptidomimetics; γ-AApeptides.
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