Flavivirus non-structural protein 5 methyltransferase (NS5-MTase)

The Flavivirus non-structural protein 5 (NS5) N-terminal methyltransferase is a critical enzyme responsible for the maturation of viral mRNA (UniProt: P29990). It catalyzes the formation of the RNA cap structure through its sequential guanylyltransferase, N7-methyltransferase, and 2'-O-methyltransferase activities (PMID: 25101572). This capping process is vital for protecting the viral genome from degradation by host exonucleases and ensuring efficient translation by the host cell machinery. Furthermore, the 2'-O-methylation of the ribose mimics host mRNA, allowing the virus to evade detection by the host's innate immune sensors, such as RIG-I and IFIT1 (PMID: 28834399). Given its essential role and high degree of structural conservation across various flaviviruses like Dengue, Zika, and West Nile, it is a primary target for the development of broad-spectrum antiviral therapies (PMID: 32659463). Current drug discovery efforts focus on small molecules that compete with the S-adenosyl-L-methionine (SAM) binding site or the RNA-binding groove to block viral replication.

Other names

Flavivirus NS5 N-terminal RNA capping enzymeNS5 methyltransferase domainFlavivirus RNA methyltransferaseNS5-MTaseFlavivirus guanylyltransferase

Inhibition of the methyltransferase activity by competing with the S-adenosyl-L-methionine (SAM) cofactor or the RNA/GTP substrate binding sites, thereby preventing the formation of the viral RNA cap and inhibiting viral translation and replication.