Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA.
Calibr at Scripps Research, 11119 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Sci Adv. 2020 May 15;6(20):eaaz4988. doi: 10.1126/sciadv.aaz4988. eCollection 2020 May.
Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono-γ-AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of α-helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists.
现有的长 α-螺旋模拟物需要保留大多数天然氨基酸残基以保持其生物活性。在这里，我们报告了具有完整非天然骨架的螺旋磺酰基-γ-AA 肽的探索，以评估其结构和功能模拟胰高血糖素样肽 1 (GLP-1) 的能力。我们的研究结果表明，具有纳摩尔效力的新型 GLP-1 受体 (GLP-1R) 激动剂的有效构建是可行的。此外，与 GLP-1 相比，所得的磺酰基-γ-AA 肽在抵抗酶降解方面也被证明具有显著的稳定性，增强了它们的生物学潜力。这种作为概念验证的 α-螺旋模拟的替代策略，可以为制备 GLP-1R 激动剂提供一种新的范例。
