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3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors.
Bobileva, Olga; Bobrovs, Raitis; Sirma, Evelina Elva; Kanepe, Iveta; Bula, Anna L; Patetko, Liene; Ramata-Stunda, Anna; Grinberga, Solveiga; Jirgensons, Aigars; Jaudzems, Kristaps.
  • 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.
Molecules ; 28(2)2023 Jan 12.
Article in English | MEDLINE | ID: covidwho-2200546
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / SARS-CoV-2 / Methyltransferases Language: English Journal subject: Biology Year: 2023 Document Type: Article Affiliation country: Molecules28020768

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / SARS-CoV-2 / Methyltransferases Language: English Journal subject: Biology Year: 2023 Document Type: Article Affiliation country: Molecules28020768