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， 这些相互作用的失调导致疾病状态。蛋白质通常利用小折叠 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， 通过模拟这些折叠结构域，我们可以特异性地抑制所选复合物的形成， 合理设计的合成分子基于这一假设，我们开发了几种 蛋白质结构域模拟物（PDM）的类别，其忠实地复制蛋白质上的结构表位 表面。这项工作为发展一种新的结构奠定了基础- 基于治疗。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， 相互作用通常是短暂的，其特征在于弱结合亲和力。模仿一个 因此，配偶体通常也导致弱结合剂，其不希望作为抗氧化剂的抑制剂。 细胞环境中的复杂途径。因此，需要一种新的方法， 设计不开始于天然复合物的基于蛋白质的结合剂。在这个NIGMS MIRA 建议，我们的目标是利用二级和三级开发PDM设计的新起点 结构接枝蛋白质展示高亲和力序列。我们将把新战略应用于 靶向治疗上重要的蛋白质-蛋白质相互作用， 包括内在无序的蛋白质。每个目标的研究将推进一般方法 以抑制蛋白质-蛋白质相互作用，并建立PDM作为跨越 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.