1. 3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors.
- Author
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Bobileva, Olga, Bobrovs, Raitis, Sirma, Evelina Elva, Kanepe, Iveta, Bula, Anna L., Patetko, Liene, Ramata-Stunda, Anna, Grinberga, Solveiga, Jirgensons, Aigars, and Jaudzems, Kristaps
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ACID derivatives , *METHYLTRANSFERASES , *SARS-CoV-2 , *BENZOIC acid , *MEMBRANE permeability (Biology) , *CELL permeability - Abstract
SARS-CoV-2 nsp14 guanine-N7-methyltransferase plays an important role in the viral RNA translation process by catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to viral mRNA cap. We report a structure-guided design and synthesis of 3-(adenosylthio)benzoic acid derivatives as nsp14 methyltransferase inhibitors resulting in compound 5p with subnanomolar inhibitory activity and improved cell membrane permeability in comparison with the parent inhibitor. Compound 5p acts as a bisubstrate inhibitor targeting both SAM and mRNA-binding pockets of nsp14. While the selectivity of 3-(adenosylthio)benzoic acid derivatives against human glycine N-methyltransferase was not improved, the discovery of phenyl-substituted analogs 5p,t may contribute to further development of SARS-CoV-2 nsp14 bisubstrate inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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