Department of Chemical, Biomolecular, and Corrosion Engineering The University of Akron, Ohio 44325, United States.
Department of Polymer Engineering The University of Akron, Ohio 44325, United States.
ACS Chem Neurosci. 2021 Apr 21;12(8):1419-1427. doi: 10.1021/acschemneuro.1c00091. Epub 2021 Mar 29.
Accumulating evidence have shown a strong pathological correlation between cardiovascular disease (CVD) and Type II diabetes (T2D), both of which share many common risk factors (e.g., hyperglycemia, hypertension, hypercoagulability, and dyslipidemia) and mutually contribute to each other. Driven by such strong CVD-T2D correlation and marginal benefits from drug development for T2D, here we proposed to repurpose a CVD drug of cloridarol as human islet amyloid peptide (hIAPP) inhibitor against its abnormal misfolding and aggregation, which is considered as a common and critical pathological event in T2D. To this end, we investigated the inhibition activity of cloridarol on the aggregation and toxicity of hIAPP using combined experimental and computational approaches. Collective experimental data from ThT, AFM, and CD demonstrated the inhibition ability of cloridarol to prevent hIAPP aggregation from its monomeric and oligomeric states, leading to the overall reduction of hIAPP fibrils up to 57% at optimal conditions. MTT and LDH cell assays also showed that cloridarol can also effectively increase cell viability by 15% and decrease cell apoptosis by 28%, confirming its protection of islet β-cells from hIAPP-induced cell toxicity. Furthermore, comparative molecular dynamics simulations revealed that cloridarol was preferentially bound to the C-terminal β-sheet region of hIAPP oligomers through a combination of hydrophobic interactions, π-π stacking, and hydrogen bonding. Such multiple site bindings allowed cloridarol to disturb hIAPP structures, reduce β-sheet content, and block the lateral association pathway of hIAPP aggregates, thus explaining experimental findings. Different from other single-target hIAPP inhibitors, cloridarol is unique in that it works as both a CVD drug and hIAPP inhibitor, which can be used as a viable structural template (especially for benzofuran) for the further development of cloridarol-based or benzofuran-based inhibitors of amyloid proteins.
越来越多的证据表明，心血管疾病（CVD）和 2 型糖尿病（T2D）之间存在很强的病理相关性，两者都有许多共同的危险因素（如高血糖、高血压、高凝状态和血脂异常），并相互促进。由于这种强烈的 CVD-T2D 相关性以及 T2D 药物开发的边际效益，我们建议将氯达洛尔（一种 CVD 药物）重新用于抑制人胰岛淀粉样肽（hIAPP），以防止其异常错误折叠和聚集，这被认为是 T2D 的一种常见和关键的病理事件。为此，我们采用实验和计算相结合的方法研究了氯达洛尔对 hIAPP 聚集和毒性的抑制活性。ThT、AFM 和 CD 的综合实验数据表明，氯达洛尔具有抑制 hIAPP 从单体和寡聚体状态聚集的能力，在最佳条件下可使 hIAPP 纤维的总体减少 57%。MTT 和 LDH 细胞检测也表明，氯达洛尔还可以有效提高细胞活力 15%，降低细胞凋亡 28%，从而证实其对胰岛 β 细胞免受 hIAPP 诱导的细胞毒性的保护作用。此外，比较分子动力学模拟表明，氯达洛尔通过疏水相互作用、π-π 堆积和氢键的结合，优先结合到 hIAPP 寡聚物的 C 端β-折叠区域。这种多部位结合使氯达洛尔能够扰乱 hIAPP 结构，降低 β-折叠含量，并阻断 hIAPP 聚集体的侧向缔合途径，从而解释了实验结果。与其他单一靶点 hIAPP 抑制剂不同，氯达洛尔的独特之处在于它既是 CVD 药物，又是 hIAPP 抑制剂，可作为基于氯达洛尔或苯并呋喃的淀粉样蛋白抑制剂的可行结构模板（尤其是苯并呋喃）。
