Department of Chemistry, University of Liverpool, L69 7ZD Liverpool, United Kingdom.
Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom.
Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1414-1419. doi: 10.1073/pnas.1816585116. Epub 2019 Jan 7.
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, , using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti- candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti- therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.
盘尾丝虫病和淋巴丝虫病是两种被忽视的热带病，它们共同影响着约 1.57 亿人，并造成严重残疾。这两种疾病都是由寄生性丝虫引起的，由于缺乏能够杀死成虫（大丝虫）的安全药物，消除工作受到限制。以前的概念验证人体试验已经证明，使用抗生素消耗超过 90%的必需线虫共生细菌 ，可以导致成年雌性寄生虫永久绝育，并产生安全的大丝虫杀灭效果。AWZ1066S 是一种高度特异的抗 候选药物，它是通过一个专注于平衡疗效、安全性和药物代谢/药代动力学（DMPK）特征的先导优化项目筛选出来的，该项目的重点是基于表型筛选的噻吩并嘧啶/喹唑啉骨架。在经过验证的感染临床前模型中，AWZ1066S 的疗效优于现有的抗 疗法，并且具有与 7 天或更短疗程兼容的 DMPK 特征。该候选药物分子具有良好的开发前景，有可能对受丝虫病影响的社区产生重大影响。
