Shenai Bhaskar R, Lee Belinda J, Alvarez-Hernandez Alejandro, Chong Pek Y, Emal Cory D, Neitz R Jeffrey, Roush William R, Rosenthal Philip J
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA.
Antimicrob Agents Chemother. 2003 Jan;47(1):154-60. doi: 10.1128/AAC.47.1.154-160.2003.
The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P(2) leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.
恶性疟原虫半胱氨酸蛋白酶恶性疟原虫蛋白酶-2和恶性疟原虫蛋白酶-3似乎是红细胞内疟原虫水解血红蛋白所必需的。先前的研究表明，恶性疟原虫蛋白酶-2的肽基乙烯砜抑制剂可阻断恶性疟原虫在培养物中的发育，并在体内发挥抗疟作用。我们现在报告39种新型乙烯砜、乙烯磺酸酯和乙烯磺酰胺半胱氨酸蛋白酶抑制剂对恶性疟原虫蛋白酶-2、恶性疟原虫蛋白酶-3和寄生虫发育抑制的构效关系。恶性疟原虫蛋白酶-2和恶性疟原虫蛋白酶-3的抑制水平通常相似，并且鉴定出了许多强效化合物。在低纳摩尔浓度下抑制恶性疟原虫发育的最佳抗疟化合物是具有P(2)亮氨酸部分的苯基乙烯砜、乙烯磺酸酯和乙烯磺酰胺。我们的结果确定了恶性疟原虫蛋白酶抑制和抗寄生虫活性的独立结构相关性，并表明肽基乙烯砜有望作为抗疟药物。
