Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors

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• 作者：Dominique Bonafoux ; Suganthini Nanthakumar ; Upul K. Bandarage ; Christine Memmott ; Derek Lowe ; Alex M. Aronov ; Govinda Rao Bhisetti ; Kenneth C. Bonanno ; Joyce Coll ; Joshua Leeman ; Christopher A. Lepre ; Fan Lu ; Emanuele Perola ; Rene Rijnbrand ; William P. Taylor ; Dean Wilson ; Yi Zhou ; Jacque Zwahlen ; Ernst ter Haar
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：59
• 期：15
• 页码：7138-7151
• 全文大小：732K
• 年卷期：0
• ISSN：1520-4804

文摘

There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 μM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 μM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.