ORGN 499 |
| Daniel A. Harki1, Jason D. Graci2, Rebecca L. Morgan2, William J. Chain1, Craig E. Cameron2, and Blake R. Peterson1. (1) Department of Chemistry, The Pennsylvania State University, 152 Davey Laboratory, Box 28, University Park, PA 16802, (2) Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802 |
| Ribavirin (1) is a synthetic ribonucleoside utilized for the treatment of hepatitis C and other viral infections. Although originally proposed to eradicate viruses by inhibiting intracellular IMPDH, recent studies have demonstrated lethal mutagenesis as the mechanism of action. Intracellular phosphorylation of ribavirin to the triphosphate yields the active species, a substrate for the viral RNA-dependent RNA polymerase (RdRP). Error-prone viral replication incorporates the triphosphate into the genome, yielding a non-natural mutation. Subsequent replication of this daughter strand promotes additional mutations as the pseudo base of ribavirin base pairs equally with both cytosine and uracil. The resultant accrual of mutations forces the virus into “error catastrophe” and loss of viability. Based upon these findings we have synthesized and evaluated a series of indole (2) and cytidine (3) derivates as novel viral mutagens. Their chemical synthesis, antiviral profiles, and kinetics of incorporation by the RdRP will be presented. |
|
Total Synthesis, Asymmetric Reactions and Syntheses, Bioorganic
9:00 AM-11:00 AM, Wednesday, March 31, 2004 Anaheim Convention Center -- Hall C, Poster
Division of Organic Chemistry |
