Development of novel small molecules to target cellular pathways

Small molecules represent powerful tools to dissect physiological and pathological states of signaling pathways, yet require characterization through X-ray crystallography. This proposal encompasses the investigation of new classes of small molecules that target difficult proteins and non-typical binding sites. This includes the development of supramolecular compounds or cyclic peptides to address “non-druggable" proteins. The main collaborative research fields are tackling Ras protein signaling with structure-guided ligand design, developing inhibitors of the Ras-binding protein PDEd, screening of a novel sp3-enriched fragment library or targeting genetic regulators. Cellular signaling will also be addressed through the structural analysis of deubiquitinating enzymes or regulators of the kinetochore. Finally, we plan to crystallize membrane proteins including GPCRs in order to understand their biological function, characterize their ligand specificity and develop novel regulators.小分子是解析信号通路生理与病理状态的有力工具，但其结构特性需通过X射线晶体学（X-ray crystallography）完成表征。本项目旨在探索靶向疑难蛋白与非典型结合位点的新型小分子类别，其中包括开发超分子化合物或环肽，以攻克“不可成药”蛋白靶点。核心合作研究领域包括：采用结构导向配体设计策略攻克Ras蛋白（Ras protein）信号通路；开发Ras结合蛋白PDEd抑制剂；筛选新型富sp3杂化片段库；以及靶向遗传调控因子。本研究还将通过解析去泛素化酶或着丝粒调控因子的结构，开展细胞信号传导相关研究。最后，本团队计划对包括G蛋白偶联受体（G protein-coupled receptors, GPCRs）在内的膜蛋白进行结晶研究，以阐明其生物学功能、表征其配体特异性，并开发新型调控因子。