MUTAGENIC NUCLEOSIDE ANALOGS WITH SUBSTITUTED RIBOSE

DESCRIPTION (provided by applicant): Research carried out at the University of Washington has demonstrated the feasibility of using a novel class of deoxynbonucleoside analogs to drive the mutation rate of HIV over the threshold for viral viability with minimal toxicity to host cells, a process termed "lethal mutagenesis" or more recently "selective viral mutagenesis." Starting from this research and publications on DNA universal bases, we have developed a novel class of ribonucleoside analogs for the treatment of RNA viruses, analogs that are incorporated by the viral RNA dependent RNA polymerase (RDRP) into the viral genome and are mutagenic for the virus. The most potent of these mutagenic ribonucleoside analogs (MRN) can effectively halt viral replication in vitro in one passage, at drug concentrations similar to that of ribavirin. Based on demonstrated activity against a paramyxovirus and a flavivirus, we expect that MRN will have a broad spectrum of antiviral activity. Having concentrated so far on modifying the nucleobase to enhance the diversity of base pairing, we now propose to modify the ribose moiety with the intention of enhancing metabolic stability and the selectivity of candidate MRN for the RDRP versus the cellular polymerases. While ribose modifications are not as well described as for deoxynboses, various substitutions are possible to the furanose ring and at the 2' to 5' positions of the ring. We would also like to test whether the L-enantiomer of a MRN can be efficiently incorporated in a growing chain of RNA by RDRP.