Peptides and Small-molecules Targeting Signaling Proteins and Protein-Protein Interfaces

靶向信号蛋白和蛋白质-蛋白质界面的肽和小分子

• 批准号: 10260506
• 负责人: Harish Vashisth
• 金额: $ 36.49万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260506
• 关键词: Address; Agonist; Allosteric Site; Binding; Cell Surface Receptors; Cone; Data; Diabetes Mellitus; Extracellular Domain; Family; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Growth; Growth Factor; Hormones; Insulin; Malignant Neoplasms; Mediator of activation protein; Metabolic; Modeling; Molecular; Pathway interactions; Peptides; Protein Family; Proteins; RGS Proteins; Research; Signal Transduction; Signaling Protein; Snail Venoms; Structure; Therapeutic Intervention; Time; Viral; Vision Disorders; Visual; base; computer studies; design; genetic regulatory protein; insulin-like peptide; mimetics; nervous system disorder; novel; novel therapeutic intervention; peptide analog; peptidomimetics; protein protein interaction; receptor; small molecule; small molecule inhibitor

Cell-surface receptors and intracellular regulatory proteins are preeminent mediators of cellular signaling as these proteins are involved in a host of interactions and pathways. Therefore, various stages of their signaling cycles provide unique opportunities for therapeutic intervention. This project presents computational studies integrated with experimental data to resolve the mechanisms of recognition of novel peptide mimetics and analogues targeting extracellular domains of receptor proteins of the insulin family and small-molecules targeting intracellular protein-protein interactions in regulatory proteins of the G-protein coupled receptor (GPCR) family. The proposed studies are timely in that several recent structural studies have revealed the binding modes of the native hormone insulin and homologous growth factor peptides and we have developed dynamics-based computational approaches that have opened the avenues for designing novel peptide-based agonists and antagonists. Toward this direction are our proposed studies of three classes of peptides: (1) synthetic insulin mimetics, (2) viral-insulin-like peptides (VILPs), and insulin-like peptides from cone snail venom. Our second research direction aims to develop small-molecule inhibitors targeting a key intracellular protein-protein interaction between regulators of G-protein signaling (RGS) proteins and the alpha-subunits of G-proteins. As opposed to the conventional approach of directly targeting the protein-protein interface, we propose to target allosteric sites on RGS proteins to inhibit the protein-protein interaction. Through preliminary studies on a model protein, we have shown that allosteric control and targeting is feasible and through this project we propose to broaden the scope of these promising studies to new protein targets involved in cancer and visual signaling. Overall, we anticipate that the mechanistic paradigms emerging from these studies will have broader applicability to other protein families and will facilitate the design of novel therapeutic strategies.

细胞表面受体和细胞内调节蛋白是细胞内信号传导的重要介质。 因为这些蛋白质参与了许多相互作用和途径。因此，我们认为， 其信号传导周期的各个阶段为治疗干预提供了独特的机会。 该项目提出了与实验数据相结合的计算研究，以解决 靶向细胞外的新型肽模拟物和类似物的识别机制 胰岛素家族受体蛋白的结构域和靶向细胞内的小分子 G蛋白偶联受体调节蛋白的蛋白质-蛋白质相互作用 家人建议的研究是及时的，因为最近的几项结构研究表明， 天然激素胰岛素和同源生长因子肽的结合模式， 已经开发出基于动力学的计算方法，为 设计新的基于肽的激动剂和拮抗剂。朝着这个方向，我们 提出了三类肽的研究：（1）合成胰岛素模拟物，（2）病毒胰岛素样肽 肽（VILP）和来自锥螺毒液的胰岛素样肽。我们的第二项研究 方向旨在开发针对关键细胞内蛋白质的小分子抑制剂-蛋白质 G-蛋白信号传导（RGS）蛋白的调节因子与 G蛋白与直接靶向蛋白质的传统方法相反， 界面，我们建议靶向RGS蛋白上的变构位点，以抑制蛋白质-蛋白质 互动通过对模型蛋白的初步研究，我们已经表明， 控制和目标是可行的，通过这个项目，我们建议扩大 这些有希望的研究涉及癌症和视觉信号的新蛋白质靶点。总的来说， 我们预计，从这些研究中出现的机制范式将有更广泛的 这将有助于其他蛋白质家族的适用性，并将有助于设计新的治疗策略。