Inhibition of mRNA methylation: an approach to specific inhibition of viral replication

Abstract

Eukaryotic mRNAs and most viral mRNAs contain very extensive modification on the 5' end consisting of the "cap," part of which is a guanine which is methylated in the 7-position. It is quite well established that the methylated cap is essential for the efficient translation of the mRNA. In a search for an effective chemotherapeutic agent, Dr. Roland Robins synthesized the compound ribavirin; this compound turned out to be an extraordinarily effective virostatic agent against both RNA and DNA viruses. Given the capping of the mRNAs produced by both types of virus, and, given the structure of ribavirin, it seemed to us that it may be fruitful to explore whether this drug might act in both cases by blocking the capping reaction. Such a mechanism indeed turned out to be a reality. We have shown that ribavirin triphosphate acts as a competitive inhibitor for the capping of mRNAs. We and others have shown that uncapped mRNAs are poorly translated. An interesting corollary confirmation of these findings is that encephalomyocarditis virus (EMC) and polio virus generate mRNAs which are not capped, and ribavirin is innocuous to these viruses. Another agent which acts as an inhibitor of mRNA methylation emerged from subsequent efforts. It is known from the work of Ian Kerr that extracts of interferon treated cells in the presence of double stranded RNA synthesize a unique 2'-5'-linked oligo (adenylic acid) 5'-triphosphate, a small trinucleotide of unusual structure, which inhibits protein synthesis. We have explored its effect on the methylation of mRNA and found it to be a potent inhibitor of methylation of the cap. Thus, two agents are known which inhibit methylation of mRNA and they may serve as prototypes for designing other such inhibitors, with a view to specific inhibition of mRNAs foreign to the host.