...胱氨酸蛋白酶罗得沙星的抑制速度,ACS Chemical Biology - X-MOL

来自 : www.x-mol.com/paper/1371679813 发布时间：2021-03-25

Viral and parasitic pathogens rely critically on cysteine proteases for host invasion, replication, and infectivity. Their inhibition by synthetic inhibitors, such as vinyl sulfone compounds, has emerged as a promising treatment strategy. However, the individual reaction steps of protease inhibition are not fully understood. Using the trypanosomal cysteine protease rhodesain as a medically relevant target, we design photoinduced electron transfer (PET) fluorescence probes to detect kinetics of binding of reversible and irreversible vinyl sulfones directly in solution. Intriguingly, the irreversible inhibitor, apart from its unlimited residence time in the enzyme, reacts 5 times faster than the reversible one. Results show that the reactivity of the warhead, and not binding of the peptidic recognition unit, limits the rate constant of protease inhibition. The use of a reversible inhibitor decreases the risk of off-target side effects not only by allowing its release from an off-target but also by reducing the rate constant of binding.
2021年3月15日ACS Chemical Biology ( IF 4.434 ) Pub Date : 2021-03-15 , DOI: 10.1021/acschembio.0c00911 Patrick Johe, Sascha Jung, Erik Endres, Christian ...战斗部反应性限制了半胱氨酸蛋白酶罗得沙星的抑制速度; Patrick Johe, Sascha Jung, Erik Endres, Christian Kersten, Collin Zimmer, Weixiang Ye, Carsten Sönnichsen, Ute A. Hellmich, Christoph Sotriffer, Tanja Schirmeister, Hannes Neuweiler; ACS Chem. Biol.; ACS Chemical Biology; X-MOL病毒和寄生虫病原体严重依赖半胱氨酸蛋白酶来感染宿主，复制和感染。它们被合成抑制剂（例如乙烯基砜化合物）抑制的作用已成为一种有前途的治疗策略。但是，蛋白酶抑制的各个反应步骤尚未完全理解。使用锥虫半胱氨酸蛋白酶罗氏蛋白酶作为医学上相关的靶标，我们设计了光诱导电子转移（PET）荧光探针，可直接检测溶液中可逆和不可逆乙烯基砜的结合动力学。有趣的是，不可逆抑制剂除了在酶中的无限停留时间外，其反应速度是可逆抑制剂的5倍。结果表明，弹头具有反应性，而不与肽段识别单元结合，限制蛋白酶抑制的速率常数。可逆抑制剂的使用不仅通过允许其从脱靶释放，而且还通过降低结合的速率常数来降低脱靶副作用的风险。战斗部反应性限制了半胱氨酸蛋白酶罗得沙星的抑制速度,ACS Chemical Biology