Viral mRNA guanylyltransferase and 2′-O-methyltransferase

The viral mRNA guanylyltransferase and 2′-O-methyltransferase are essential enzymatic components of the viral capping apparatus, responsible for the post-transcriptional modification of the 5′ end of viral mRNA [2, 3]. This process, known as capping, involves the addition of a guanosine cap via a 5′-5′ triphosphate linkage (guanylyltransferase activity) and the subsequent methylation of the ribose at the 2′-O position of the first transcribed nucleotide (2′-O-methyltransferase activity) [5, 10]. These modifications are crucial for protecting viral RNA from exonuclease degradation, ensuring efficient recognition by the host translation machinery, and evading the host's innate immune system [3, 8]. Uncapped or improperly methylated viral RNA (lacking 2′-O-methylation) is recognized as "non-self" by cytosolic sensors such as RIG-I and IFIT1, which trigger a potent interferon response [3, 9]. In many viral families, such as Flaviviridae (e.g., Dengue, Zika) and Mononegavirales (e.g., RSV, Ebola), these activities are performed by a single multifunctional protein like NS5 or the L protein, while in Coronaviridae, they are distributed across separate non-structural proteins [5, 8]. Inhibitors of these enzymes, including nucleoside analogs like ribavirin and SAM-competitive small molecules, disrupt viral replication by preventing the production of functional, "stealthy" viral transcripts [1, 8].

Other names

Viral mRNA capping enzymeVCENon-structural protein 5 (NS5)Large protein (L)nsp14/nsp16 complexmRNA guanylyltransferasemRNA 2′-O-methyltransferase

Inhibition of viral mRNA capping and methylation, preventing viral protein synthesis and facilitating immune recognition of viral RNA.