Most of single positive strand RNA viruses have evolved strategies in order to decorate the 5′ end of their own genome by a cap structure mimicking the eukaryotic messenger RNA. This structure plays several key biological functions such as protection of RNA from 5′-exoribonucleoases and initiation of the RNA translation into proteins. Moreover the cap is a marker of ‘self’ preventing detection by the cellular innate immunity mechanism. Thus viruses such as flaviviruses and coronaviruses code for RNA capping pathway mimicking that of eukaryotic cells. These viruses produce a subset of enzymatic activities including a RNA 5′-triphosphatase, a guanilyltransferase (GTase) and two RNA cap methyltransferases (MTases) [8]. After the cap (GpppN) is set by the GTase, a first methylation occurs at N7 position of the guanine by a N7-MTase in the presence of methyl donor S-adenosyl methionine (SAM) yielding to a cap-0 (7mGpppN) followed by a further methylation that is achieved by a 2′-O-MTase at 2′- position of the ribose of the first transcribed nucleotide in RNA yielding cap-1 (7mGpppNm) (Scheme 1 ). The N7- and 2′-O-methylation of the viral RNA cap are key events for the viral infection as their inhibition might limit the synthesis of viral proteins and support virus elimination by stimulation of the immune response [9]. Therefore it is now admitted that the viral MTases are considered as attractive targets for the development of antiviral therapy [10,11]. Few viral MTase inhibitors have been developed so far, however SAM-mimetics acting as competitors against the MTase co-substrate merit attention. Indeed SAM analogs such as sinefungin, 5′-methylthioadenosine (MTA) or S-adenosyl homocysteine (SAH) inhibit most of viral MTases with a potent efficiency but with a total lack of specificity [12]. This is certainly due to the high conservation of the shape and location of the SAM binding pocket in the human or different viral RNA MTases which share a common Rossman fold organization [13]. The rarity of specific inhibitors for viral MTases constitutes a stimulating challenge for new antiviral therapy but also for functional studies of these fascinating enzymes.
Scheme 1 Schematic representation of the 2′-O-methylation of the cap structure at nucleoside N1 at 5′-end of mRNA to form Cap-1 RNA. General structure of compounds mimicking the 2′-O-methylation transition state between N1 of mRNA (adenosine in green) and SAM (adenosine in blue).