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首页> 外文期刊>The Journal of biological chemistry >Structural Basis for Inhibition of Cathepsin B Drug Target from the Human Blood Fluke, Schistosoma mansoni
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Structural Basis for Inhibition of Cathepsin B Drug Target from the Human Blood Fluke, Schistosoma mansoni

机译：从人血吸虫，血吸虫麦森抑制组织素B药物靶向的结构基础

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Schistosomiasis caused by a parasitic blood fluke of the genus Schistosoma afflicts over 200 million people worldwide. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated peptidase that digests host blood proteins as a source of nutrients. It is under investigation as a drug target. To further this goal, we report three crystal structures of SmCB1 complexed with peptidomimetic inhibitors as follows: the epoxide CA074 at 1.3 ? resolution and the vinyl sulfones K11017 and K11777 at 1.8 and 2.5 ? resolutions, respectively. Interactions of the inhibitors with the subsites of the active-site cleft were evaluated by quantum chemical calculations. These data and inhibition profiling with a panel of vinyl sulfone derivatives identify key binding interactions and provide insight into the specificity of SmCB1 inhibition. Furthermore, hydrolysis profiling of SmCB1 using synthetic peptides and the natural substrate hemoglobin revealed that carboxydipeptidase activity predominates over endopeptidolysis, thereby demonstrating the contribution of the occluding loop that restricts access to the active-site cleft. Critically, the severity of phenotypes induced in the parasite by vinyl sulfone inhibitors correlated with enzyme inhibition, providing support that SmCB1 is a valuable drug target. The present structure and inhibitor interaction data provide a footing for the rational design of anti-schistosomal inhibitors.
机译：由血吸虫属的寄生虫血吸虫引起的血吸虫病折磨了全世界的200万人。 Schistosoma Mansoni Codepsin B1（SMCB1）是一种肠道相关的肽酶，其消化宿主血液蛋白作为营养素的来源。它是作为药物目标的调查。为了进一步实现这一目标，我们将三种SMCB1晶体结构报告为肽染色体抑制剂，如下：环氧化物CA074在1.3时？分辨率和乙烯基砜K11017和K11777为1.8和2.5？分别决议。通过量子化学计算评估抑制剂与活性位点裂缝底座的相互作用。这些数据和用乙烯基砜衍生物面板抑制曲线鉴定关键结合相互作用，并对SMCB1抑制的特异性提供洞察力。此外，使用合成肽和天然底物血红蛋白的SMCB1的水解分析显示，羧基肽酶活性占主肽分解，从而展示了阻塞环限制接近活性位点裂缝的贡献。批判性地，通过与酶抑制相关的乙烯基砜抑制剂在寄生虫中诱导的表型的严重性，提供SMCB1是有价值的药物靶标的支持。本结构和抑制剂相互作用数据为抗血吸虫抑制剂的合理设计提供了基础。

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