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强效工具，但需通过X射线晶体学（X-ray crystallography）完成表征。本研究计划针对靶向难靶向蛋白与非典型结合位点的新型小分子类别开展研究，其中包括开发超分子化合物或环肽，以攻克“不可成药”（non-druggable）蛋白。核心合作研究方向包括：借助结构导向配体设计解析Ras蛋白信号通路、开发Ras结合蛋白PDEd的抑制剂、筛选新型sp3富集片段库（sp3-enriched fragment library），以及靶向遗传调控因子。本研究还将通过对去泛素化酶（deubiquitinating enzymes）或动粒（kinetochore）调控因子的结构分析，探究细胞信号传导机制。最后，计划对包括G蛋白偶联受体（GPCRs）在内的膜蛋白开展晶体学研究，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。