AI Article Synopsis

  • There are no current treatments for severe infections caused by human polyomaviruses like JCV and BKV.
  • Researchers reported the first crystal structure of the helicase from JCV large T antigen, which helped in designing new inhibitors that target these viruses.
  • The study optimized initial inhibitors, significantly increasing their effectiveness and demonstrated antiviral activity without significant toxicity in cell tests.

Article Abstract

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.

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http://dx.doi.org/10.1021/acs.jmedchem.6b00486DOI Listing

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