Viral mRNA guanylyltransferase and mRNA 2′-O-methyltransferase (VCE/2'-O-MTase)

Viral mRNA guanylyltransferase and mRNA 2′-O-methyltransferase are essential enzymes that coordinate the formation of the 5′ cap structure on viral messenger RNA (Decroly et al., 2012). This capping process involves the addition of a guanosine moiety and subsequent methylation at the N7 and 2′-O positions, which is critical for protecting viral transcripts from exonucleolytic degradation and ensuring their recognition by the host's translational machinery (Viswanathan et al., 2020). Beyond stability, the 2′-O-methylation of the first nucleotide (forming the Cap-1 structure) serves as a vital immune evasion strategy, as it prevents the viral RNA from being recognized as "non-self" by host innate immune sensors like RIG-I and MDA5 (Daffis et al., 2010). These enzymes are highly conserved across several pathogenic virus families, including Coronaviridae and Flaviviridae, making them attractive targets for broad-spectrum antiviral therapy (Dong et al., 2014). Inhibition of these targets leads to the production of uncapped or improperly capped RNA, which is either rapidly degraded or triggers a robust host interferon response that halts viral replication. Current drug discovery efforts focus on small molecules that compete with the methyl donor S-adenosyl-L-methionine or target the unique RNA-binding pockets of the viral enzymes to achieve selectivity over human homologs (UniProt P0C6X7).

Other names

mRNA capping enzymeRNA guanylyltransferase (GTase)Nucleoside-2'-O-methyltransferase (2'-O-MTase)NSP16/NSP10 complexNS5 methyltransferase domainVP39D1/D12 complex

Inhibition of viral mRNA 5' capping and 2'-O-methylation, resulting in impaired viral protein synthesis and enhanced recognition of viral RNA by host pattern recognition receptors (Decroly et al., 2012).