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

基本信息

批准号：
10581865
负责人：
Harish Vashisth
金额：
$ 24.08万
依托单位：
UNIVERSITY OF NEW HAMPSHIRE
依托单位国家：
美国
项目类别：
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/10581865
关键词：
Agonist Allosteric Site Amber Architecture Award Binding Binding Sites Biochemical Cell Surface Receptors Computer Hardware Computer software Computers Computing Methodologies Cone Contractor Data Development Docking Employee Environment Epitopes Equipment Extracellular Domain Family Feasibility Studies Future G-Protein-Coupled Receptors GTP-Binding Protein Regulators GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Growth Factor High Performance Computing Homology Modeling Hormones Insulin Insulin Receptor Knowledge Ligand Binding Malignant Neoplasms Mediating Mediator of activation protein Methods Modeling Molecular Occupations Parents Pathway interactions Peptides Protein Family Proteins RGS Proteins Research Research Personnel SHPS-1 protein Security Services Side Signal Transduction Signaling Protein Snail Venoms Specificity Structure Students Study models Supercomputing System Technology Therapeutic Therapeutic Intervention Time Training Update Variant Viral Visual Visualization Yeasts analog antagonist base biophysical techniques career networking chemical property computer studies cost data centers data management design extracellular genetic regulatory protein graduate student inhibitor insulin-like peptide large scale simulation member mimetics models and simulation molecular dynamics novel novel therapeutic intervention operation peptide analog peptidomimetics petabyte programs protein complex protein protein interaction receptor recruit simulation simulation software small molecule small molecule inhibitor success tool

项目摘要

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重要的介质信号传导，因为这些蛋白质参与许多相互作用和途径。所以，其信号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 (GPCR) 调节蛋白中的蛋白质-蛋白质相互作用家庭。拟议的研究是及时的，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，我们开发了基于动力学的计算方法，为设计新型的基于肽的激动剂和拮抗剂。我们的方向就是朝着这个方向提议对三类肽进行研究：(1) 合成胰岛素模拟物，(2) 病毒胰岛素样肽肽（VILP）和锥蜗牛毒液中的胰岛素样肽。我们的第二个研究方向旨在开发针对关键细胞内蛋白质-蛋白质的小分子抑制剂 G 蛋白信号 (RGS) 蛋白调节因子与 α 亚基之间的相互作用 G-蛋白。与直接靶向蛋白质-蛋白质的传统方法相反接口，我们建议针对 RGS 蛋白上的变构位点来抑制蛋白质-蛋白质相互作用。通过对模型蛋白质的初步研究，我们发现变构控制和瞄准是可行的，通过这个项目，我们建议扩大这些有前途的研究涉及癌症和视觉信号传导的新蛋白质靶点。全面的，我们预计这些研究中出现的机械范式将具有更广泛的应用前景。适用于其他蛋白质家族并将有助于设计新的治疗策略。