Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, Tampa, FL, USA.
Chembiochem. 2022 Nov 18;23(22):e202200298. doi: 10.1002/cbic.202200298. Epub 2022 Sep 12.
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.
我们小组最近开发的磺酰基-γ-AA 肽已被证明是一类新的非天然折叠体，具有明确的螺旋结构，并已被证明可以模拟蛋白质螺旋结构域并破坏与生物医学相关的蛋白质-蛋白质相互作用 (PPIs)。基于我们在最近的一份报告中的设计理念，我们发现了两种类似的磺酰基-γ-AA 肽 V2 和 V3，它们旨在模拟已知与 VEGFR 直接相互作用的 VEGF N 端螺旋 α1。有趣的是，V2 被证明具有促血管生成作用，而 V3 被证明是一种有效的血管生成抑制剂。我们推测，两种分子分别与 VEGFR1 和 VEGFR2 的选择性结合导致了不同的血管生成信号。V2 和 V3 具有显著的抗蛋白水解降解能力、相对较小的尺寸以及易于用各种功能基团进行修饰的特点，可作为开发潜在治疗剂和分子探针的先导分子。这些发现强调了磺酰基-γ-AA 肽作为模拟 α-螺旋结构域的替代范例，以在未来调节各种蛋白质-蛋白质相互作用。
