Ochiana Stefan O, Bland Nicholas D, Settimo Luca, Campbell Robert K, Pollastri Michael P
Department of Chemistry and Chemical Biology, Northeastern University, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA, 02115, USA.
Chem Biol Drug Des. 2015 May;85(5):549-64. doi: 10.1111/cbdd.12443. Epub 2014 Nov 18.
Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.
环核苷酸磷酸二酯酶（PDEs）已被确定为人类和布氏锥虫（人类非洲锥虫病的病原体）药物开发的重要酶靶点。考虑到这一点，我们最近报道了一系列人类磷酸二酯酶抑制剂的分析，表明人类PDE4抑制剂往往对锥虫磷酸二酯酶TbrPDEB1表现出最佳效力。其中包括GSK - 256066，一种有效的人类PDE4抑制剂和TbrPDEB1的弱抑制剂。在本报告中，我们描述了这种化学类型的构效关系研究结果，从而发现了对TbrPDEB1效力提高且对布氏锥虫细胞生长有微摩尔级抑制作用的类似物。我们通过将新抑制剂分子对接至最近报道的TbrPDEB1无配体结构来解释效力趋势。本文的研究将为未来将人类PDE抑制剂重新用作抗锥虫药物的努力提供参考。
