Protein Domain Mimics as Modulators of Biomolecular Interactions

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 这些相互作用的错误调节会导致疾病状态。蛋白质经常利用小折叠 用于识别其他生物分子的结构域。指导我们研究的基本假设是 通过模仿这些折叠域，我们可以特异性抑制选定的复合物形成 合理设计的合成分子。基于这个假设，我们开发了几种 忠实再现蛋白质结构表位的蛋白质结构域模拟物 (PDM) 类别 表面。这项工作为新型结构的开发奠定了基础—— based therapeutics.到目前为止，我们的努力主要集中在模仿天然结合伙伴 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，并且具有弱结合亲和力的特征。 Mimicry of one 因此，伴侣通常也会导致弱结合物，这作为抑制剂是不合需要的。 细胞环境中的复杂途径。因此，需要一种新的方法来合理地 基于蛋白质的粘合剂的设计并非从天然复合物开始。 In this NIGMS MIRA 根据提案，我们的目标是利用二级和三级技术为 PDM 设计开发新的起点 结构移植蛋白展示高亲和力序列。我们将把新的战略应用到 靶向治疗上重要的蛋白质-蛋白质相互作用，但没有有效的抑制剂， 包括本质上无序的蛋白质。每个目标的研究将推进一般方法 抑制蛋白质-蛋白质相互作用，并将 PDM 建立为跨越 小分子和蛋白质之间的分子大小空间。

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.