以G蛋白为靶点的天然环状氧酯肽的全合成及构效关系研究

G proteins are molecular switch of G protein-coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The complex natural products, cyclic depsipeptides YM-254890 and FR900359 are the only known selective inhibitors of the Gq subfamily of G proteins, but they are not generally available. Recently, we have successfully achieved the first total synthesis of YM-254890 and FR900359 in mini gram scale, later pharmacology characterization showed the IC50 of synthetic YM-254890 and FR900359 on Gq inhibition were 95 nM and 33 nM, respectively, which are identical to natural products. This project aiming at exploring the efficient synthesis of YM-254890, as well as performing the structure activity relationship studies,by using either new synthetic strategies, or optimize the strategy that we have developed, to establish a fast and efficient synthetic route towards this cyclic depsipeptide. With the optimized strategy, we will perform the structure-activity relationship study of YM-254890, including studies on the N-methylated peptide bonds and ester bonds within the molecular backbone, unnatural β-Hle side chain and unsaturated terminal C=C bond, to develop simplified, highly potent and selective Gq inhibitors, as well as providing theoretical and practical basis for further structure optimization. Meanwhile, this project will represent new pharmaceutical tools for explorative studies of G protein functional mechanism.

G蛋白作为分子开关在G蛋白偶联受体(GPCR)的信号传递中发挥着关键作用，调节着大量重要生理功能。环状天然氧酯肽YM-254890 和 FR900359是现存仅有的选择性Gq抑制剂，但其来源受限。申请人近期首次完成了YM-254890 和 FR900359毫克级全合成，并证实合成的YM-254890和FR900359对Gq的IC50低达95nM和33nM，与天然产物一致。本课题以进一步探索YM-254890的高效合成，以及开展构效关系研究为目的，通过设计新的合成路线，或优化现有合成策略来实现该分子的快速合成，并利用优化的合成策略对YM-254890进行构效关系研究，重点考察分子骨架中的甲基化肽键和酯键、非天然β-羟基亮氨酸侧链及不饱合末端双键对化合物活性的影响，寻找结构简化的高活性、选择性Gq抑制剂，为进一步结构优化打下基础，同时也为G蛋白的作用机理研究提供工具药物。