Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors
| Autor: | Joshua R. Leeman, Joyce T. Coll, Upul K. Bandarage, Derek B. Lowe, Alex Aronov, Christine Memmott, Jacque Zwahlen, Kenneth C. Bonanno, Emanuele Perola, William P. Taylor, Christopher A. Lepre, Dean M. Wilson, Yi Zhou, Rene Rijnbrand, Dominique Bonafoux, Fan Lu, Bhisetti Govinda Rao, Ernst ter Haar, Suganthini Nanthakumar |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine viruses JC virus medicine.disease_cause Structure-Activity Relationship 03 medical and health sciences Drug Discovery medicine Structure–activity relationship Enzyme Inhibitors Cytotoxicity Dose-Response Relationship Drug Molecular Structure biology Drug discovery Chemistry DNA Helicases virus diseases Helicase JC Virus Virology Molecular biology BK virus 030104 developmental biology BK Virus Vero cell biology.protein Molecular Medicine Triazolopyridine |
| Zdroj: | Journal of Medicinal Chemistry. 59:7138-7151 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b00486 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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