Inhibition of Human Islet Amyloid Polypeptide Aggregation

人胰岛淀粉样多肽聚集的抑制

• 批准号: 9340249
• 负责人: Feng Ding
• 金额: $ 36.2万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340249
• 关键词: Amyloid; Amyloid Fibrils; Ants; Artificial nanoparticles; Beta Cell; Biodistribution; Biological Availability; Cell Death; Computer Simulation; Cytoplasmic Granules; Dendrimers; Disease; Drug Delivery Systems; Drug usage; Elements; Engineering; Environment; Generations; Human; In Vitro; Individual; Insulin; Knowledge; Lead; Length; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pharmaceutical Preparations; Physiological; Polymers; Property; Research; Solubility; Structure of beta Cell of islet; System; Therapeutic; Time; Validation; design; diabetic; granule cell; improved; inhibitor/antagonist; insight; islet amyloid polypeptide; nanomedicine; nanoparticle; novel; novel therapeutic intervention; peptide hormone; polyphenol; prevent; small molecule; small molecule inhibitor; water solubility

Abstract Mounting evidence suggests that the aggregation of islet amyloid polypeptide (IAPP) is associated with β-cell death in type-2 diabetes (T2D). IAPP, a 37-residue peptide hormone secreted by β-cells, readily forms amyloid fibrils in vitro at µM concentrations. The aggregates of IAPP, either insoluble amyloid fibrils or soluble oligomers, are found toxic to β-cells. Inhibition of IAPP aggregation is an attractive therapeutic strategy to prevent β-cell death and stop the progression of diabetic conditions in T2D. Interestingly, no apparent IAPP aggregates are observed in healthy individuals where IAPP is stored in β-cell granules at mM concentrations. Therefore, physiological conditions of β-cell granules natively inhibit amyloid aggregation of IAPP. Disruption of the inhibitive environment of β-cell granules may lead to the accumulation of toxic IAPP aggregates, causing β- cell death and the diabetic condition of insulin deficiency in T2D. Molecular mechanisms of the native inhibition of hIAPP aggregation are largely unknown, which limit the design of novel therapeutic approaches that either promote or mimic the native inhibition. In addition, several naturally-occurring small-molecule polyphenols displayed inhibitory effects on hIAPP aggregation. However, many of these small molecules have low water solubility, which limits their bioavailability and biodistribution. Knowledge of the mechanism of action of these polyphenols may help design de novo small-molecule drugs that can inhibit hIAPP aggregation with higher efficacy and solubility. Further more, our preliminary studies combining in silico modeling with in vitro and ex vivo characterization indicated that the generation-3 polyamidoamin (PAMAM) dendrimer, a polymeric nanoparticle commonly used for drug delivery, could also inhibit hIAPP aggregation. Our results pointed to a promising nanomedicinal approach for both efficient loading of ant-amyloid drug and inhibitory effect on hIAPP aggregation. In this MIRA application, the PI proposes the following three projects to uncover various inhibition mechanisms of hIAPP aggregation: 1) to delineate the inhibitive mechanism of the environmental elements of granules on IAPP aggregation; 2) to uncover the inhibition mechanism of hIAPP aggregation by small-molecule polyphenols; and 3) to explore dendritic nanoparticles with increased small-molecule loading and inhibitive effects on hIAPP aggregation. The PI lab will combine computational modeling with experimental characterization and validation. Computational modeling can help bridge the gaps of time and length scales between experimental observations and the underlying molecular systems, providing not only molecular insight to experimental observations but also offering experimentally-testable hypotheses. Such a combined computational and experimental approach can improve research efficiency and shorten discovery cycle. The outcome of the proposed studies will help design therapeutic strategies to either promote or mimic the native inhibition (Project 1), novel small-molecule inhibitors with enhanced anti-amyloid efficacy (Project 2), and engineered NPs with both high drug delivery and enhanced anti-aggregation properties (Project 3).

抽象的 越来越多的证据表明胰岛淀粉样多肽 (IAPP) 的聚集与 β 细胞相关 2 型糖尿病 (T2D) 中的死亡。IAPP 是一种由 β 细胞分泌的 37 个残基肽激素，可形成淀粉样蛋白。 µM 浓度的体外原纤维 IAPP 的聚集体，无论是不溶性淀粉样原纤维还是可溶性淀粉样原纤维。 寡聚物被发现对 β 细胞有毒，抑制 IAPP 聚集是一种有吸引力的治疗策略。 预防 β 细胞死亡并阻止 T2D 糖尿病病情的进展，但没有明显的 IAPP。 在健康个体中观察到聚集体，其中 IAPP 以 mM 浓度储存在 β 细胞颗粒中。 因此，β细胞颗粒的生理条件天然地抑制 IAPP 的淀粉样蛋白聚集。 β细胞颗粒的抑制环境可能导致有毒IAPP聚集体的积累，引起β- T2D 中细胞死亡和胰岛素缺乏的糖尿病状况。天然抑制的分子机制。 hIAPP 聚集的机制在很大程度上是未知的，这限制了治疗新方法的设计 此外，几种天然存在的小分子多酚可以促进或模拟天然抑制作用。 对 hIAPP 聚集表现出抑制作用，然而，许多这些小分子的水分含量较低。 溶解度，这限制了它们的生物利用度和生物分布。了解这些药物的作用机制。 多酚可能有助于从头设计小分子药物，以更高的抑制 hIAPP 聚集 此外，我们的初步研究将计算机模拟与体外和实验相结合。 体内表征表明，第 3 代聚酰胺胺 (PAMAM) 树枝状聚合物是一种聚合物 通常用于药物输送的纳米颗粒也可以抑制 hIAPP 聚集。 纳米药物方法有望有效负载抗淀粉样蛋白药物并抑制 hIAPP 在此 MIRA 应用中，PI 提出了以下三个项目来揭示各种抑制作用。 hIAPP聚集机制：1）阐明环境因素的抑制机制 颗粒对IAPP聚集的影响2)揭示小分子抑制hIAPP聚集的机制 多酚；3) 探索具有增加的小分子负载和抑制作用的树枝状纳米粒子 对 hIAPP 聚合的影响 PI 实验室将计算模型与实验相结合。 表征和验证可以帮助弥合时间和长度尺度的差距。 实验观察和底层分子系统之间的联系，不仅提供分子洞察 实验观察，同时也提供了这样一个可通过实验检验的假设。 计算和实验方法可以提高研究效率并缩短发现周期。 拟议研究的结果将有助于设计治疗策略，以促进或模仿天然 抑制（项目 1），具有增强抗淀粉样蛋白功效的新型小分子抑制剂（项目 2），以及 工程纳米粒子具有高药物输送和增强的抗聚集特性（项目 3）。