Peptidomimetic Vinyl Heterocyclic Inhibitors of Cruzain Effect Antitrypanosomal Activity
作者:Bala C. Chenna、Linfeng Li、Drake M. Mellott、Xiang Zhai、Jair L. Siqueira-Neto、Claudia Calvet Alvarez、Jean A. Bernatchez、Emily Desormeaux、Elizabeth Alvarez Hernandez、Jana Gomez、James H. McKerrow、Jorge Cruz-Reyes、Thomas D. Meek
DOI:10.1021/acs.jmedchem.9b02078
日期:2020.3.26
disease. We describe here a new series of reversible, but time-dependent, inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl-heterocycles meant to provide replacements for the irreversible reactive "warheads" of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl-heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe- scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine
Cruzain是一种寄生虫原生动物Trypanosoma cruzi的必需半胱氨酸蛋白酶,是恰加斯病的重要药物靶标。我们在这里描述了一系列新的可逆但时间依赖性的克鲁赞蛋白酶抑制剂,该抑制剂由附加至乙烯基杂环的二肽支架组成,旨在为克鲁赞蛋白酶的乙烯基砜灭活剂提供不可逆的反应性“弹头”。含Cbz-Phe-Phe / homoPhe-骨架并带有乙烯基-2-嘧啶,乙烯基-2-吡啶和乙烯基-2-(N-甲基)-吡啶基的拟肽乙烯基杂环抑制剂(PVHI)赋予了可逆的,时间依赖性的抑制克鲁萨因(Ki * = 0.1-0.4μM)。与人类组织蛋白酶B,L和S相比,这些Cruzain抑制剂显示出中等至出色的选择性,并且对人细胞没有明显的毒性,但在布鲁氏锥虫锥虫的细胞培养中有效(EC50 = 1-15μM),并在感染的小鼠心肌成纤维细胞中消除了克鲁氏锥虫(EC50 = 5-8μM)。PVHIs是一类新的Cruza