Jones Brian D, Tochowicz Anna, Tang Yinyan, Cameron Michael D, McCall Laura-Isobel, Hirata Ken, Siqueira-Neto Jair L, Reed Sharon L, McKerrow James H, Roush William R
Department of Chemistry, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
Department of Pathology and Sandler Center for Drug Discovery, University of California-San Francisco , 1700 Fourth Street, San Francisco, California 94158-2250, United States.
ACS Med Chem Lett. 2015 Dec 15;7(1):77-82. doi: 10.1021/acsmedchemlett.5b00336. eCollection 2016 Jan 14.
A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cruzain inhibitors. Co-crystal structures of the oxyguanidine analogues WRR-666 (4) and WRR-669 (7) bound to cruzain demonstrated different binding interactions with the cysteine protease, depending on the aryl moiety of the P1' inhibitor subunit. Specifically, these data demonstrate that WRR-669 is bound noncovalently in the crystal structure. This represents a rare example of noncovalent inhibition of a cysteine protease by a vinyl sulfone inhibitor.
合成了一系列半胱氨酸蛋白酶抑制剂WRR-483的氧胍类似物，并针对原生动物寄生虫克氏锥虫的主要半胱氨酸蛋白酶克氏锥虫蛋白酶进行了评估。对这些类似物的动力学分析表明，它们与先前制备的乙烯砜克氏锥虫蛋白酶抑制剂具有相当的效力。与克氏锥虫蛋白酶结合的氧胍类似物WRR-666（4）和WRR-669（7）的共晶体结构显示，根据P1'抑制剂亚基的芳基部分，它们与半胱氨酸蛋白酶具有不同的结合相互作用。具体而言，这些数据表明WRR-669在晶体结构中以非共价方式结合。这代表了乙烯砜抑制剂对半胱氨酸蛋白酶进行非共价抑制的罕见例子。
