Total Synthesis of Covalent Cysteine Protease Inhibitor N‑Desmethyl Thalassospiramide C and Crystallographic Evidence for Its Mode of Action

A total synthesis of N-desmethyl thalassospiramide C, a unique strained macrocyclic proteobacterial depsipeptide, enabled a detailed crystallographic study of its covalent complex with cathepsin K, a member of a medicinally important family of cysteine proteases. The study provides support for the mechanism of action, and the insight gained can be used for structure-based drug design targeting these calpain proteases.

本研究完成了N-去甲基海链藻酰胺C（N-desmethyl thalassospiramide C）的全合成，该化合物是一类独特的变形菌门来源的张力性大环缩酚肽（depsipeptide）。依托该合成产物，我们得以对其与药用重要半胱氨酸蛋白酶（cysteine proteases）家族成员组织蛋白酶K（cathepsin K）形成的共价复合物开展细致的晶体学研究。本研究为该类化合物的作用机制提供了实验支撑，所获得的研究见解可用于针对此类钙蛋白酶（calpain proteases）的基于结构的药物设计。