12:00 AM
Oct 11, 2012
 |  BC Innovations  |  Targets & Mechanisms

Closing time for HCV protease

Astex Pharmaceuticals Inc. has used its fragment-based drug discovery platform to identify a new allosteric binding site on the full-length HCV NS3/4A protein and thinks compounds that bind the site can inhibit the protein's helicase activity in addition to its proteolytic activity.1 The result could be molecules with better efficacy than existing HCV drugs that target the protease active site.

The full-length HCV NS3/4A protein consists of a protease domain linked to a helicase domain. According to Astex president, director and cofounder Harren Jhoti, R&D efforts to target the NS3/4A complex have previously focused on compounds that target the active site of the protein's protease domain due to screening limitations-it is more technically challenging to express and crystallize the full-length protein than individual domains for screening purposes.

Celia Schiffer, a professor of biochemistry and molecular pharmacology and director of the Center for AIDS Research at the University of Massachusetts Medical School, noted that another reason the HCV field has focused on developing compounds against the individual domains of the NS3/4A protein stems from the view that the protein's helicase and protease functions are essentially independent of one another.

Despite not working with the full protein, efforts to inhibit the HCV NS3/4A protease active site have borne fruit-notably the approvals of Victrelis boceprevir from Merck & Co. Inc. and Incivek telaprevir from Vertex Pharmaceuticals Inc. in May of last year.

There are at least 10 HCV NS3/4A protease inhibitors in various stages of clinical development, including three in Phase III trials.

Jhoti said compounds that target the same site on the HCV protein are likely to be affected by the same resistance mutations. Thus, rather than joining an already crowded space by pursuing compounds against the protease active site, the Astex...

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