Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Astbury Centre for Structural Molecular Biology, School of Physics and Astronomy, University of Leeds, Leeds, LS2 9JT, UK.
Nat Commun. 2022 Feb 24;13(1):1040. doi: 10.1038/s41467-022-28660-7.
Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that the aggregation of both peptides involves primary nucleation, secondary nucleation and elongation. We also report the discovery of two structurally distinct small-molecule modulators of hIAPP assembly, one delaying the aggregation of wt hIAPP, but not S20G; while the other enhances the rate of aggregation of both variants at substoichiometric concentrations. Investigation into the inhibition mechanism(s) using chemical kinetics, native mass spectrometry, fluorescence titration, SPR and NMR revealed that the inhibitor retards primary nucleation, secondary nucleation and elongation, by binding peptide monomers. By contrast, the accelerator predominantly interacts with species formed in the lag phase. These compounds represent useful chemical tools to study hIAPP aggregation and may serve as promising starting-points for the development of therapeutics for T2D.
人胰岛淀粉样多肽（hIAPP）会自组装成淀粉样纤维，沉积在 2 型糖尿病（T2D）患者的胰岛中。在这里，我们应用化学动力学研究野生型 hIAPP 及其更具淀粉样特性的天然变体 S20G 的淀粉样组装机制。我们表明，这两种肽的聚集都涉及初级成核、次级成核和延伸。我们还报告了两种结构不同的小分子 hIAPP 组装调节剂的发现，一种可延迟 wt hIAPP 的聚集，但不延迟 S20G；而另一种则可在亚化学计量浓度下增强两种变体的聚集速率。使用化学动力学、天然质谱、荧光滴定、SPR 和 NMR 研究抑制机制表明，抑制剂通过结合肽单体来抑制初级成核、次级成核和延伸。相比之下，加速剂主要与滞后期形成的物质相互作用。这些化合物是研究 hIAPP 聚集的有用化学工具，可能成为 T2D 治疗药物开发的有前途的起点。
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