Protein Domain Mimics as Modulators of Biomolecular Interactions

作为生物分子相互作用调节剂的蛋白质结构域模拟物

• 批准号: 10798527
• 负责人: Paramjit S Arora
• 金额: $ 7.68万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10798527
• 关键词: Administrative Supplement; Affinity; Affinity Chromatography; Binding; Biological Process; Complex; Detection; Development; Disease; Epitopes; Event; Foundations; Funding; Gene Expression Regulation; Grant; Joints; Membrane Proteins; Methods; National Institute of General Medical Sciences; Pathway interactions; Protein Engineering; Protein Inhibition; Proteins; RNA-Protein Interaction; Research; Services; Signal Transduction; Structure; System; Tertiary Protein Structure; Therapeutic; Therapeutic Agents; Time; Work; design; fast protein liquid chromatography; inhibitor; instrument; mimicry; molecular size; novel strategies; parent grant; pointed protein; pressure; protein protein interaction; protein purification; rational design; small molecule; synthetic protein; targeted treatment; therapeutic candidate

Abstract Interactions of proteins with other biomolecules regulate fundamental cellular events and misregulation of these interactions leads to disease states. Proteins often utilize small, folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these folded domains we can specifically inhibit chosen complex formation with rationally designed synthetic molecules. Based on this hypothesis, we have developed several classes of Protein Domain Mimics (PDMs) that faithfully reproduce structural epitopes on protein surfaces. This work has created a foundation for the development of a new class of structure– based therapeutics. Our efforts so far have focused on mimicry of a natural binding partner to inhibit complex formation. A challenge with this approach is that natural protein-protein interactions are often transient and characterized by weak binding affinities. Mimicry of one partner, therefore, often also leads to weak binders, which are undesirable as inhibitors of complex pathways in the cellular context. A new approach is, therefore, required for rational design of protein-based binders that does not begin with natural complexes. In this NIGMS MIRA proposal, we aim to develop new starting points for PDM design by utilizing secondary and tertiary structure-grafted protein displays for high affinity sequences. We will apply the new strategy to target therapeutically important protein-protein interactions for which there are no potent inhibitors, including intrinsically disordered proteins. Studies in each Aim will advance general approaches to inhibit protein-protein interactions and establish PDMs as distinct constructs spanning the molecular size space between small molecules and proteins.

摘要 蛋白质与其他生物分子的相互作用调节基本的细胞事件和这些事件的误调节 相互作用导致疾病状态。蛋白质通常利用小的折叠结构域来识别其他蛋白质。 生物分子指导我们研究的基本假设是，通过模仿这些折叠结构域， 用合理设计的合成分子特异性抑制所选复合物的形成。基于此 假设，我们已经开发了几类蛋白质结构域模拟物（PDM）， 蛋白质表面的结构表位。这项工作为新班级的发展奠定了基础 基于结构的治疗方法。到目前为止，我们的努力集中在模仿天然结合伴侣， 抑制复合物形成。这种方法的一个挑战是，天然蛋白质-蛋白质相互作用通常是 短暂的并且以弱结合亲和力为特征。因此，模仿一个伴侣往往也会导致 弱结合剂，其作为细胞环境中复杂途径的抑制剂是不期望的。一种新的方法 因此，需要合理设计不开始于天然复合物的基于蛋白质的结合剂。 在本NIGMS MIRA提案中，我们的目标是通过利用二次和 三级结构接枝的蛋白质展示高亲和力序列。我们将把新的战略应用于目标 治疗上重要的蛋白质-蛋白质相互作用，没有有效的抑制剂，包括 内在无序的蛋白质每个目标的研究将推进抑制蛋白质-蛋白质的一般方法 相互作用，并将PDM建立为跨越小分子之间的分子大小空间的不同构建体。 分子和蛋白质。