Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
J Med Chem. 2010 Feb 25;53(4):1763-73. doi: 10.1021/jm901633v.
A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.
在发现克氏锥虫寄生虫是恰加斯病的病因 100 年后，治疗仍然受到疗效有限、毒性和耐药性出现的困扰。已经证明，抑制主要的克氏锥虫半胱氨酸蛋白酶——克氏锥虫蛋白酶，是治疗这种被忽视疾病的一种有前途的药物发现途径。在这里，我们证实了一种非肽类四氟苯甲氧基甲基酮克氏锥虫蛋白酶抑制剂在没有明显毒性的情况下，可显著改善急性恰加斯病小鼠模型的症状。高分辨率晶体结构证实了抑制模式，并揭示了这种新型抑制剂类别的关键结合相互作用。随后的结构导向优化导致尽管分子量增加很少或没有，但抑制剂类似物的效力得到提高。在细胞培养中评估类似物显示出增强的活性。这些结果表明，非肽类四氟苯甲氧基甲基酮克氏锥虫蛋白酶抑制剂有可能满足改善恰加斯病化疗的迫切需求。
