Repurposing a Cardiovascular Disease Drug of Cloridarol as hIAPP Inhibitor
Repurposing a Cardiovascular Disease Drug of Cloridarol as hIAPP Inhibitor
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将心血管疾病药物 Cloridarol 重新用作 hIAPP 抑制剂
DOI：
10.1021/acschemneuro.1c00091
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发表时间：
2021
影响因子：
5
通讯作者：
Zheng, Jie
中科院分区：
文献类型：
--
作者：
Tang, Yijing;Liu, Yonglan;Zhang, Yanxian;Zhang, Dong;Gong, Xiong;Zheng, Jie
越来越多的证据表明，心血管疾病（CVD）和II型糖尿病（T2 D）之间存在很强的病理相关性，两者都有许多共同的风险因素（例如，高血糖症、高血压、高凝状态和血脂异常），并且相互促进。由于CVD-T2 D之间的强相关性和T2 D药物开发的边际效益，我们提出将氯立达罗的CVD药物重新用作人胰岛淀粉样肽（hIAPP）抑制剂，以对抗其异常错误折叠和聚集，这被认为是T2 D中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立达醇对hIAPP 1 - 37聚集和毒性的抑制活性。来自ThT、AFM和CD的集体实验数据证明了氯立达醇阻止hIAPP从其单体和寡聚体状态聚集的抑制能力，导致在最佳条件下hIAPP原纤维的总体减少高达57%。MTT和LDH细胞测定也显示，氯立达醇还可以有效地增加细胞活力15%，减少细胞凋亡28%，证实其保护胰岛β细胞免受hIAPP诱导的细胞毒性。此外，比较分子动力学模拟显示，氯立达醇通过疏水相互作用、π-π堆积和氢键的组合优先结合到hIAPP寡聚体的C-末端β-折叠区域。这种多位点结合允许氯立达酚干扰hIAPP结构，减少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。与其他单靶点hIAPP抑制剂不同，氯立达罗的独特之处在于它同时作为CVD药物和hIAPP抑制剂，可用作可行的结构模板（特别是苯并呋喃），用于进一步开发基于氯立达罗或苯并呋喃的淀粉样蛋白抑制剂。
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 hIAPP1–37using 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.