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Design, synthesis and functional characteristics of low molecular weight proline-rich motif (PRM) mimetics recognized by PRM binding domains

PRM 结合域识别的低分子量富含脯氨酸基序 (PRM) 模拟物的设计、合成和功能特征

基本信息

批准号：
35756057
负责人：
Dr. Michael Beyermann
金额：
--
依托单位：
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2007
资助国家：
德国
起止时间：
2006-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/35756057?language=en
关键词：
Design synthesis functional characteristics low

项目摘要

A major reason for the difficulty in modulating protein-protein interactions (PPI) by small molecules is that they typically possess flat and rather large binding interfaces, displaying little concavity. These interactions are classified according to their specificity. An important dass of such protein domains exhibits solvent exposed regions that are able to bind the proline-rich motifs (PRM) of their target proteins. Currently, six distinct families of PRM-binding domains (PRO) (Src-homology 3 (SH3) domains, WW domains, EVH1 (Ena/VASP homology 1) domains, GYF domains, UEV (ubiquitin E2 variant) domains and profilin are known. Present in many multi-component signaling complexes, such PRDs recognize characteristic patterns of proline residues by means of stacked aromatic amino acids on their surface. Additionally, the specificity of this interaction is influenced by flanking binding epitopes. The aim of this project is to discover new specific modulators of the human EVH1 domain, the SH3-domain of the src kinase Fyn, and the YAP-WW domain, based on a new polyproline II helix mimetic structure and structural modifications developed and characterized during the previous project phase. These compounds represent a new dass of PRM mimetics and may serve äs starting points for the development of specific, pharmacologically relevant inhibitors of PRM- mediated protein-protein interaction (PPI). Additionally, we search for new lead compounds to modulate the three families of domain by screening the ChemBioNet library and by virtual screening of specifically assembled focused libraries. The project combines rational, structurebased small molecule design, structural biology, stereoselective synthesis of novel scaffolds, peptide synthesis, new scaffold-based ligation strategies, compound screening and functional characterization of the PRO modulators.

通过小分子调节蛋白质-蛋白质相互作用（PPI）的困难的主要原因是它们通常具有平坦且相当大的结合界面，显示出很少的重叠。这些相互作用根据其特异性进行分类。一类重要的蛋白质结构域具有溶剂暴露区域，这些区域能够结合其靶蛋白的富含脯氨酸的基序（PRM）。目前，已知六个不同的PRM结合结构域（PRO）家族（Src-同源3（SH 3）结构域、WW结构域、EVH 1（Ena/VASP同源1）结构域、GYF结构域、UEV（泛素E2变体）结构域和profilin）。存在于许多多组分信号复合物中，这样的PRD通过其表面上堆叠的芳香族氨基酸识别脯氨酸残基的特征模式。此外，这种相互作用的特异性受侧翼结合表位的影响。该项目的目的是发现新的人类EVH 1结构域，src激酶Fyn的SH 3结构域和YAP-WW结构域的特异性调节剂，基于新的聚脯氨酸II螺旋模拟结构和在前一项目阶段开发和表征的结构修饰。这些化合物代表了一类新的PRM模拟物，并可能成为开发PRM介导的蛋白质-蛋白质相互作用（PPI）的特异性、非特异性相关抑制剂的起点。此外，我们寻找新的先导化合物，以调节三个家庭的结构域的筛选ChemBioNet库和虚拟筛选专门组装的集中库。该项目结合了合理的、基于结构的小分子设计、结构生物学、新型支架的立体选择性合成、肽合成、基于新支架的连接策略、化合物筛选和PRO调节剂的功能表征。