3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors.

Autor: Bobileva O; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia., Bobrovs R; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia., Sirma EE; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia., Kanepe I; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia., Bula AL; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia., Patetko L; Faculty of Biology, University of Latvia, LV-1004 Riga, Latvia., Ramata-Stunda A; Faculty of Biology, University of Latvia, LV-1004 Riga, Latvia., Grinberga S; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia., Jirgensons A; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia., Jaudzems K; Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2023 Jan 12; Vol. 28 (2). Date of Electronic Publication: 2023 Jan 12.
DOI: 10.3390/molecules28020768
Abstrakt: SARS-CoV-2 nsp14 guanine- N 7-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.
Databáze: MEDLINE
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