Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly.
Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly.
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DOI：
10.1038/s41467-022-28660-7
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发表时间：
2022-02-24
影响因子：
16.6
通讯作者：
Radford SE
中科院分区：
文献类型：
--
作者：
Xu Y;Maya-Martinez R;Guthertz N;Heath GR;Manfield IW;Breeze AL;Sobott F;Foster R;Radford SE
人胰岛淀粉样多肽(HIAPP)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了野生型hIAPP及其更具淀粉样变性的自然变异体S20G的淀粉样蛋白组装机制。我们发现这两种多肽的聚集过程包括一次成核、二次成核和伸长。我们还报告了hIAPP组装的两个结构不同的小分子调制器的发现，一个延缓了wt hIAPP的聚集，但不是S20G；而另一个提高了两个变体在亚化学计量浓度下的聚集速度。采用化学动力学、天然质谱学、荧光滴定、固相共振和核磁共振等方法对缓蚀剂的缓蚀机理(S)进行了研究，结果表明，缓蚀剂通过与多肽单体结合，延缓了一次成核、二次成核和延伸率。相比之下，加速器主要与滞后阶段形成的物种相互作用。这些化合物代表了研究hIAPP聚集的有用的化学工具，并可能成为T2D治疗学发展的有希望的起点。在这里，作者进行了化学动力学研究，揭示了hIAPP及其变体S20G的聚集涉及二次成核。两个具有新型支架的小分子通过结合不同的分子物种来抑制或加速聚集。
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. Here the authors carry out chemical kinetic studies revealing that aggregation of hIAPP and its variant S20G involves secondary nucleation. Two small molecules with novel scaffolds are shown to inhibit or accelerate aggregation by binding different molecular species.
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影响因子：
5
作者：
Rodriguez Camargo DC;Chia S;Menzies J;Mannini B;Meisl G;Lundqvist M;Pohl C;Bernfur K;Lattanzi V;Habchi J;Cohen SI;Knowles TPJ;Vendruscolo M;Linse S
通讯作者：
Linse S
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
13.6
作者：
Habchi J;Arosio P;Perni M;Costa AR;Yagi-Utsumi M;Joshi P;Chia S;Cohen SI;Müller MB;Linse S;Nollen EA;Dobson CM;Knowles TP;Vendruscolo M
通讯作者：
Vendruscolo M
DOI：
10.1073/pnas.84.23.8628
发表时间：
1987-12-01
影响因子：
11.1
作者：
COOPER, GJS;WILLIS, AC;REID, KBM
通讯作者：
REID, KBM
影响因子：
14.8
作者：
Feng, Brian Y.;Toyama, Brandon H.;Shoichet, Brian K.
通讯作者：
Shoichet, Brian K.