Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
ChemMedChem. 2009 Dec;4(12):2060-9. doi: 10.1002/cmdc.200900262.
There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62,000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.
目前迫切需要开发新的药物来治疗热带寄生虫病，例如由布氏锥虫引起的非洲人类锥虫病。该酶硫醇还原酶（TryR）是这些生物体中的一个潜在的药物靶点。在此，我们报告了针对 T. brucei TryR 的 62000 种化合物库的筛选。进一步的工作旨在优化从酶和全寄生虫筛选以及哺乳动物细胞计数器筛选中产生的两个新型化合物系列的效力和选择性。这两个系列都含有喹啉或嘧啶并吡嗪骨架，均对酶和寄生虫的生长产生了低微摩尔的抑制作用。本文讨论了用类药性分子抑制 TryR 所面临的挑战。
