%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Hausdorff, M.
%A Delpal, A.
%A Barelier, S.
%A Nicollet, L.
%A Canard, B.
%A Touret, F.
%A Colmant, Agathe
%A Coutard, B.
%A Vasseur, J. J.
%A Decroly, E.
%A Debart, F.
%T Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases
%D 2023
%L fdi:010088101
%G ENG
%J European Journal of Medicinal Chemistry
%@ 0223-5234
%K 7-deaza-adenine ; Arylsulfonamide ; Bisubstrate ; SARS-CoV-2 ; RNA cap ; Methyltransferase ; Structure -guided design
%M ISI:001007491000001
%P 115474 [19 ]
%R 10.1016/j.ejmech.2023.115474
%U https://www.documentation.ird.fr/hor/fdi:010088101
%> https://www.documentation.ird.fr/intranet/publi/2023-07/010088101.pdf
%V 256
%W Horizon (IRD)
%X 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.
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