Research Project
6691768
DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) has already caused a global epidemic, but the worst may be to come. According to the CDC nearly 4 million people have been infected with HCV in the U.S. alone. A fourfold increase in the number of adults diagnosed with chronic HCV infection is projected up to 2015. Most persons with chronic HCV infection have yet to be diagnosed and are likely to come to medical attention in the next decade. Although about a dozen of agents have been claimed to be active against HCV, currently there is no effective treatment available. During the course of our search for nucleosides that may inhibit replication of bovine viral diarrhea virus (BVDV), used as an HCV surrogate, we discovered potent inhibitory activity of 3-beta-D-ribofuranosyl-9,5'-cyclopurine derivative, e.g. nucleoside derivative containing the bicyclo[4.2.1]nonane ring system. This compound also shows potent and selective activity in the HCV replicon system. Clearly, this compound is not an inhibitor of HCV RNA polymerase and its mechanism of action is currently unknown. SAR-based synthetic efforts are proposed by examination of 3 classes of derivatives of the lead compound with modification at the sugar moiety and/or the pyridone ring of the purine base as well as the triazole moiety. Since certain nucleosides with 2'-dehydro-2'-methyI-D-ribofuranose showed a potent anti-HCV activity the lead compound(s) will be substituted with the 2'-"beta"-(up)-methyl group. The modification of the six-membered ring and the triazole ring of the base will show the importance of the base on the anti-HCV activity of proposed compounds. It is expected that new compounds with improved anti-HCV potential will emerge from these studies and proposed SAR may help to understand the mechanism of action of this class of compounds.
