Rugel Anastasia, Tarpley Reid S, Lopez Ambrosio, Menard Travis, Guzman Meghan A, Taylor Alexander B, Cao Xiaohang, Kovalskyy Dmytro, Chevalier Frédéric D, Anderson Timothy J C, Hart P John, LoVerde Philip T, McHardy Stanton F
Department of Pathology and Laboratory Medicine, Department of Biochemistry and Structural Biology, and Greehey Children's Cancer Research Institute, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, United States.
Center for Innovative Drug Discovery, University of Texas at San Antonio, Department of Chemistry, One UTSA Circle, San Antonio, Texas 78249, United States.
ACS Med Chem Lett. 2018 Sep 14;9(10):967-973. doi: 10.1021/acsmedchemlett.8b00257. eCollection 2018 Oct 11.
Schistosomiasis is a major human parasitic disease afflicting more than 250 million people, historically treated with chemotherapies praziquantel or oxamniquine. Since oxamniquine is species-specific, killing but not other schistosome species ( or ) and evidence for drug resistant strains is growing, research efforts have focused on identifying novel approaches. Guided by data from X-ray crystallographic studies and worm killing assays on oxamniquine, our structure-based drug design approach produced a robust structure-activity relationship (SAR) program that identified several new lead compounds with effective worm killing. These studies culminated in the discovery of compound , which demonstrated broad-species activity in killing (75%), (40%), and (83%).
血吸虫病是一种主要的人类寄生虫病，折磨着超过2.5亿人，历史上一直用化疗药物吡喹酮或奥沙尼喹进行治疗。由于奥沙尼喹具有物种特异性，只能杀死曼氏血吸虫，而不能杀死其他血吸虫物种（埃及血吸虫或日本血吸虫），并且耐药菌株的证据越来越多，研究工作集中在寻找新的方法上。在X射线晶体学研究数据和对奥沙尼喹的杀线虫试验的指导下，我们基于结构的药物设计方法产生了一个强大的构效关系（SAR）程序，该程序鉴定出了几种具有有效杀线虫作用的新先导化合物。这些研究最终发现了化合物，该化合物在杀死曼氏血吸虫（75%）、埃及血吸虫（40%）和日本血吸虫（83%）方面表现出广泛的物种活性。
