Zaware Nilesh, Sharma Hitesh, Yang Jie, Devambatla Ravi Kumar Vyas, Queener Sherry F, Anderson Karen S, Gangjee Aleem
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06511, United States.
ACS Med Chem Lett. 2013 Oct 4;4(12):1148-1151. doi: 10.1021/ml400208v.
Infection by the parasite (tg) can lead to toxoplasmosis in immunocompromised patients such as organ transplant, cancer and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in , and represents a potential target to combat infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species and specificity is significantly more challenging. We discovered novel substituted-9-pyrimido[4,5-]indoles - with single-digit nanomolar K for tgTS, two of which, and , are 28- and 122-fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data. These results show, for the very first time, that in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections.
寄生虫（tg）感染可导致免疫功能低下患者（如器官移植患者、癌症患者和艾滋病毒/艾滋病患者）患弓形虫病。双功能胸苷酸合成酶-二氢叶酸还原酶（TS-DHFR）酶对（寄生虫名称未明确，原文此处有误）的核苷酸合成至关重要，是对抗（寄生虫名称未明确，原文此处有误）感染的潜在靶点。虽然针对二氢叶酸还原酶已实现药物的物种选择性，但胸苷酸合成酶在物种间更为保守，实现特异性更具挑战性。我们发现了新型取代的9-嘧啶并[4,5-]吲哚——对tgTS的K值为个位数纳摩尔，其中两种化合物（化合物名称未明确，原文此处有误）对人TS（hTS）的选择性分别为28倍和122倍。本文介绍了这些化合物的合成方法、它们与tgTS-DHFR复合物的结构，以及结合测量结果和细胞培养数据。这些结果首次表明，尽管hTS和寄生虫TS的活性位点残基高度保守，但已通过新型结构实现了特异性，并为开发针对寄生虫感染的选择性药物提供了新靶点（TS）。
