Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Nature. 2010 Apr 1;464(7289):728-32. doi: 10.1038/nature08893.
African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.
非洲昏睡病或人类非洲锥虫病，由布氏锥虫引起，每年导致约 30000 人死亡。这种疾病的可用治疗方法效果不佳，安全性也不能接受，特别是在寄生虫感染中枢神经系统的疾病晚期。在这里，我们报告了一个分子靶标的验证和相关先导化合物的发现，这些化合物有可能解决这种缺乏合适治疗方法的问题。抑制该靶标-布氏锥虫 N-豆蔻酰转移酶-导致在体外和体内迅速杀死锥虫，并治愈小鼠的锥虫病。这些高亲和力抑制剂结合到酶的肽底物口袋中，并抑制锥虫中的蛋白质豆蔻酰化。鉴定出的化合物具有有前途的药物特性，为开发治疗这种毁灭性疾病的口服药物提供了机会。我们的研究验证了 T. brucei N-豆蔻酰转移酶作为人类非洲锥虫病有希望的治疗靶点。
