Hausdorff M., Delpal A., Barelier S., Nicollet L., Canard B., Touret F., Colmant Agathe, Coutard B., Vasseur J. J., Decroly E., Debart F. (2023). Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases. European Journal of Medicinal Chemistry, 256, p. 115474 [19 p.]. ISSN 0223-5234.
Titre du document
Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases
Année de publication
2023
Auteurs
Hausdorff M., Delpal A., Barelier S., Nicollet L., Canard B., Touret F., Colmant Agathe, Coutard B., Vasseur J. J., Decroly E., Debart F.
Source
European Journal of Medicinal Chemistry, 2023,
256, p. 115474 [19 p.] ISSN 0223-5234
The COVID-19 pandemic reveals the urgent need to develop new therapeutics targeting the SARS-CoV-2 replication machinery. The first antiviral drugs were nucleoside analogues targeting RdRp and protease inhibitors active on nsp5 Mpro. In addition to these common antiviral targets, SARS-CoV-2 codes for the highly conserved protein nsp14 harbouring N7-methyltransferase (MTase) activity. Nsp14 is involved in cap N7-methylation of viral RNA and its inhibition impairs viral RNA translation and immune evasion, making it an attractive new antiviral target. In this work, we followed a structure-guided drug design approach to design bisubstrates mimicking the S-adenosylmethionine methyl donor and RNA cap. We developed adenosine mimetics with an Narylsulfonamide moiety in the 5 '-position, recently described as a guanine mimicking the cap structure in a potent adenosine-derived nsp14 inhibitor. Here, the adenine moiety was replaced by hypoxanthine, N6-methyladenine, or C7-substituted 7-deaza-adenine. 26 novel adenosine mimetics were synthesized, one of which selectively inhibits nsp14 N7-MTase activity with a subnanomolar IC50 (and seven with a single-digit nanomolar IC50). In the most potent inhibitors, adenine was replaced by two different 7-deaza-adenines bearing either a phenyl or a 3-quinoline group at the C7-position via an ethynyl linker. These more complex compounds are barely active on the cognate human N7-MTase and docking experiments reveal that their selectivity of inhibition might result from the positioning of their C7 substitution in a SAM entry tunnel present in the nsp14 structure and absent in the hN7-MTase. These compounds show moderate antiviral activity against SARS-CoV-2 replication in cell culture, suggesting delivery or stability issue.
Plan de classement
Sciences fondamentales / Techniques d'analyse et de recherche [020]
;
Santé : généralités [050]
;
Entomologie médicale / Parasitologie / Virologie [052]
Localisation
Fonds IRD [F B010088101]
Identifiant IRD
fdi:010088101
