Chenna Bala C, Li Linfeng, Mellott Drake M, Zhai Xiang, Siqueira-Neto Jair L, Calvet Alvarez Claudia, Bernatchez Jean A, Desormeaux Emily, Alvarez Hernandez Elizabeth, Gomez Jana, McKerrow James H, Cruz-Reyes Jorge, Meek Thomas D
Department of Biochemistry & Biophysics, Texas A&M University, 301 Old Main Drive, College Station, Texas 77843, United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
J Med Chem. 2020 Mar 26;63(6):3298-3316. doi: 10.1021/acs.jmedchem.9b02078. Epub 2020 Mar 17.
Cruzain, an essential cysteine protease of the parasitic protozoan, , is an important drug target for Chagas 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, and vinyl-2-(-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (* = 0.1-0.4 μM). These cruzain inhibitors exhibited moderate to excellent selectivity versus human cathepsins B, L, and S and showed no apparent toxicity to human cells but were effective in cell cultures of (EC = 1-15 μM) and eliminated in infected murine cardiomyoblasts (EC = 5-8 μM). PVHIs represent a new class of cruzain inhibitors that could progress to viable candidate compounds to treat Chagas disease and human sleeping sickness.
克鲁兹蛋白酶是寄生原生动物的一种必需半胱氨酸蛋白酶，是恰加斯病的重要药物靶点。我们在此描述了一系列新的可逆但具有时间依赖性的克鲁兹蛋白酶抑制剂，它们由连接到乙烯基杂环上的二肽支架组成，旨在替代克鲁兹蛋白酶乙烯砜失活剂中不可逆的反应性“弹头”。含有Cbz-Phe-Phe/高苯丙氨酸支架以及乙烯基-2-嘧啶、乙烯基-2-吡啶和乙烯基-2-（-甲基）-吡啶基团的拟肽乙烯基杂环抑制剂（PVHIs）对克鲁兹蛋白酶具有可逆的、时间依赖性抑制作用（* = 0.1 - 0.4 μM）。这些克鲁兹蛋白酶抑制剂对人组织蛋白酶B、L和S表现出中度至优异的选择性，对人细胞无明显毒性，但在锥虫细胞培养中有效（EC = 1 - 15 μM），并在感染的小鼠心肌成纤维细胞中清除锥虫（EC = 5 - 8 μM）。PVHIs代表了一类新的克鲁兹蛋白酶抑制剂，有望发展成为治疗恰加斯病和人类昏睡病的可行候选化合物。
