Development of Protein Surface Binding, Low Entropy Oligomers

描述（由申请人提供）： 我们将测试这样的假设，即我们可以快速开发具有低构象熵的寡聚配体，其通过依次扩增寡聚体上的药效团以高亲和力（Kd < 10 nM）结合蛋白质表面上的浅裂缝和凹槽。我们将从具有已知结合结构的肽开始，并将肽药效团的关键侧链转移到寡聚双肽支架上，以产生对靶蛋白具有中等或良好亲和力的分子。然后我们将一次延伸一个单体的二肽，并筛选少量的单体立体异构体和侧链，以鉴定对受体具有更好亲和力的配体。通过重复该过程两次或三次，我们将鉴定出对靶受体具有低纳摩尔或亚纳摩尔解离常数的基于双肽的配体。我们将在三种靶蛋白上检验这一假设：hDMX、HIV gp 41和七跨膜结合的G蛋白偶联受体GLP-1 R。然后，我们将与其他人合作，以评估这些化合物的体内活性。 公共卫生相关性：我们开发的蛋白质结合双肽配体将通过破坏蛋白质-蛋白质相互作用来调节它们结合的蛋白质的功能。它们将为生物学家研究靶蛋白在细胞中的作用提供有用的工具。它们也可能被开发为涉及靶蛋白的疾病的新疗法。我们将开发针对三种蛋白质的双肽。第一个目标是hDMX，一种与癌症有关的蛋白质。第二个目标是HIV gp 41，我们将开发双肽，防止HIV与人类细胞融合，并可用于治疗HIV。第三个目标是七跨膜G蛋白偶联受体GLP-1 R：我们将开发作为GLP-1 R激动剂和拮抗剂的双肽，可用于治疗2型糖尿病。

DESCRIPTION (provided by applicant): We will test the hypothesis that we can rapidly develop oligomeric ligands with low conformational entropy that bind shallow crevices and grooves on protein surfaces with high affinity (Kd < 10 nM) by sequentially expanding a pharmacophore on the oligomer. We will start with a peptide with a known bound structure and transfer the key side-chains of the peptide pharmacophore onto an oligomeric bis-peptide scaffold to create molecules with moderate or good affinity for the target protein. We will then extend the bis-peptide one monomer at a time and screen a small number of monomer stereoisomers and side-chains to identify ligands with better affinity for the receptor. By repeating this process two or three times we will identify bis-peptide based ligands with low nanomolar or subnanomolar dissociation constants for the target receptor. We will test the hypothesis on three target proteins: hDMX, HIV gp41 and the seven-transmembrane bound G-protein coupled receptor GLP-1R. We will then collaborate with others to evaluate the in vivo activity of these compounds. PUBLIC HEALTH RELEVANCE: The protein binding bis-peptide ligands that we develop will modulate the functions of the proteins they bind by disrupting protein-protein interactions. They will be useful tools for biologists to study the roles of the target proteins in cells. They may also be developed as new therapeutics for diseases that involve the target proteins. We will develop bis-peptides that target three proteins. The first target is hDMX a protein involved in cancer. The second target is HIV gp41, we will develop bis-peptides that prevent fusion of HIV with human cells and could be used to treat HIV. The third target is the seven-transmembrane G-protein coupled receptor GLP-1R: we will develop bis-peptides that act as agonists and antagonists of GLP-1R which could be used to treat type 2 diabetes.