SARS-CoV-2 N7-methyltransferase inhibitors: Towards selective and potent antivirals

Recent studies have identified nsp14 N7-methyltransferase (N7-MTase) as a promising therapeutic target for the development of new antiviral agents against SARS-CoV-2. Utilising S-adenosyl-L-methionine (SAM) as a methyl donor, N7-MTase mediates the first methylation step in viral RNA capping, which is necessary for the replication of SARS-CoV-2 and its immune evasion. To design selective and potent inhibitors of CoV nsp14 N7-MTase, various research groups have focused on targeting the nsp14 binding site for SAM. In this paper, promising CoV N7-MTase inhibitors designed to date are analysed with a particular focus on SAM/S-adenosyl-L-homocysteine (SAH) analogues, which can be further extended to occupy the RNA binding site and/or the adjacent lateral cavity. The structure-activity relationship (SAR) data and binding modes of the inhibitors are also investigated. This study highlights limitations that currently hinder the development of effective antiviral agents, notably limited selectivity and cellular activity, and discusses potential strategies to address them. In particular, the design of C-nucleosides has shown promising results, although no inhibitor has reached clinical trials yet. Thus, further efforts are necessary to identify viable drug candidates.