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 对这些相互作用的错误调控会导致疾病状态。蛋白质通常利用小折叠 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，我们可以通过以下方式特别地抑制选定的络合物的形成 合理设计的合成分子。基于这一假设，我们发展了几个 能忠实复制蛋白质表面结构表位的蛋白质结构域模拟物(PDM) 表面。这项工作为发展一类新的结构奠定了基础-- 以治疗学为基础。到目前为止，我们的努力主要集中在模仿具有天然约束力的合作伙伴 抑制复合体的形成。这种方法的一个挑战是，天然蛋白质-蛋白质 相互作用通常是暂时的，并且具有弱结合亲和力的特点。一个人的模仿 因此，伴侣通常还会导致粘结剂较弱，这是不受欢迎的，因为它是 在细胞环境中的复杂路径。因此，Rational需要一种新的方法 设计基于蛋白质的粘合剂，而不是从天然复合体开始。在这张NIGMS Mira中 建议，我们的目标是开发新的起点，利用二次和第三级的产品数据管理设计 结构接枝的蛋白质显示出高亲和力序列。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，但没有有效的抑制剂， 包括天生无序的蛋白质。对每个目标的研究将推动一般方法的发展 为了抑制蛋白质之间的相互作用，并将PDMS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.