Structures of SARS-CoV-2 N7-methyltransferase with DOT1L and PRMT7 inhibitors provide a platform for new antivirals.

The RNA N7-methyltransferase (MTase) activity of SARS-CoV-2's nsp14 protein is essential for viral replication and is a target for the development of new antivirals. Nsp14 uses S-adenosyl methionine (SAM) as the methyl donor to cap the 5' end of the SARS-CoV-2 mRNA and generates S-adenosyl homocysteine (SAH) as the reaction byproduct. Due to the central role of histone MTases in cancer, many SAM/SAH analogs with properties of cell permeability have recently been developed for the inhibition of these MTases. We have succeeded in identifying two such compounds (SGC0946 and SGC8158) that display significant antiviral activity and bind to the SARS-CoV-2 nsp14 N7-MTase core. Unexpectedly, crystal structures of SGC0946 and SGC8158 with the SARS-CoV-2 nsp14 N7-MTase core identify them as bi-substrate inhibitors of the viral MTase, co-occupying both the SAM and RNA binding sites; positing novel features that can be derivatized for increased potency and selectivity for SARS-CoV-2 nsp14. Taken together, the high-resolution structures and the accompanying biophysical and viral replication data provide a new avenue for developing analogs of SGC0946 and SGC8158 as antivirals. Author summary: SARS-CoV-2 and its variants have led to millions of deaths globally. The RNA N7-methyltransferase activity of SARS-CoV-2's nsp14 protein is essential for viral replication and represents a promising target for antiviral drug development. In this study, we identified two compounds (SGC0946 and SGC8158) with significant antiviral activity that bind to the SARS-CoV-2 nsp14 N7-MTase core. Co-crystal structures of these compounds with the N7-MTase core were determined, revealing features that can be modified for increased potency and selectivity. These findings provide an avenue for developing SGC0946/SGC8158 analogs as antivirals. [ABSTRACT FROM AUTHOR]