Keke Chai, Jian Yang, Ying Tu, Junjie Wu, Kang Fang, Shuo Shi and Tianming Yao*,
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引用次数: 0
Abstract
Direct inhibitor of tau aggregation has been extensively studied as potential therapeutic agents for Alzheimer’s disease. However, the natively unfolded structure of tau complicates the structure-based ligand design, and the relatively large surface areas that mediate tau–tau interactions in aggregation limit the potential for identifying high-affinity ligand binding sites. Herein, a group of isatin-pyrrolidinylpyridine derivative isomers (IPP1–IPP4) were designed and synthesized. They are like different forms of molecular “transformers”. These isatin isomers exhibit different inhibitory effects on tau self-aggregation or even possess a depolymerizing effect. Our results revealed for the first time that the direct inhibitor of tau protein aggregation is not only determined by the previously reported conjugated structure, substituent, hydrogen bond donor, etc. but also depends more importantly on the molecular shape. In combination with molecular docking and molecular dynamics simulations, a new inhibition mechanism was proposed: like a “molecular clip”, IPP1 could noncovalently bind and fix a tau polypeptide chain at a multipoint to prevent the transition from the “natively unfolded conformation” to the “aggregation competent conformation” before nucleation. At the cellular and animal levels, the effectiveness of the inhibitor of the IPP1 has been confirmed, providing an innovative design strategy as well as a lead compound for Alzheimer’s disease drug development.
We propose that molecular deformation is a key factor in the screening aggregation inhibitor for intrinsic disordered protein tau. We designed and synthesized four isomers with different shapes by a modular combination of isatin and pyrrolidinylpyridine and verified that they have different binding abilities to tau and inhibitory activities against tau aggregation. Our results will provide a new direction for developing a tau aggregation inhibitor.
作为阿尔茨海默病的潜在治疗药物,对 tau 聚合的直接抑制剂进行了广泛的研究。然而,tau 的原生展开结构使基于结构的配体设计变得复杂,而且在聚集过程中介导 tau-tau 相互作用的相对较大的表面积限制了确定高亲和力配体结合位点的潜力。在此,我们设计并合成了一组异汀-吡咯烷基吡啶衍生物异构体(IPP1-IPP4)。它们就像不同形式的分子 "变压器"。这些异构体对 tau 的自我聚集具有不同的抑制作用,甚至具有解聚作用。我们的研究结果首次揭示了对 tau 蛋白聚集的直接抑制作用不仅取决于之前报道的共轭结构、取代基、氢键供体等,更重要的是取决于分子形状。结合分子对接和分子动力学模拟,我们提出了一种新的抑制机制:IPP1 就像一个 "分子夹",可以非共价地在多点上结合并固定 tau 多肽链,从而阻止其在成核前从 "原生展开构象 "过渡到 "聚集能力构象"。在细胞和动物水平上,IPP1 抑制剂的有效性已得到证实,为阿尔茨海默氏症药物开发提供了一种创新的设计策略和先导化合物。
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.