@article{fdi:010088101,
  title = {{S}tructure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 {N}7-methyltransferases},
  author = {{H}ausdorff, {M}. and {D}elpal, {A}. and {B}arelier, {S}. and {N}icollet, {L}. and {C}anard, {B}. and {T}ouret, {F}. and {C}olmant, {A}gathe and {C}outard, {B}. and {V}asseur, {J}. {J}. and {D}ecroly, {E}. and {D}ebart, {F}.},
  editor = {},
  language = {{ENG}},
  abstract = {{T}he {COVID}-19 pandemic reveals the urgent need to develop new therapeutics targeting the {SARS}-{C}o{V}-2 replication machinery. {T}he first antiviral drugs were nucleoside analogues targeting {R}d{R}p and protease inhibitors active on nsp5 {M}pro. {I}n addition to these common antiviral targets, {SARS}-{C}o{V}-2 codes for the highly conserved protein nsp14 harbouring {N}7-methyltransferase ({MT}ase) activity. {N}sp14 is involved in cap {N}7-methylation of viral {RNA} and its inhibition impairs viral {RNA} translation and immune evasion, making it an attractive new antiviral target. {I}n this work, we followed a structure-guided drug design approach to design bisubstrates mimicking the {S}-adenosylmethionine methyl donor and {RNA} cap. {W}e developed adenosine mimetics with an {N}arylsulfonamide moiety in the 5 '-position, recently described as a guanine mimicking the cap structure in a potent adenosine-derived nsp14 inhibitor. {H}ere, the adenine moiety was replaced by hypoxanthine, {N}6-methyladenine, or {C}7-substituted 7-deaza-adenine. 26 novel adenosine mimetics were synthesized, one of which selectively inhibits nsp14 {N}7-{MT}ase activity with a subnanomolar {IC}50 (and seven with a single-digit nanomolar {IC}50). {I}n the most potent inhibitors, adenine was replaced by two different 7-deaza-adenines bearing either a phenyl or a 3-quinoline group at the {C}7-position via an ethynyl linker. {T}hese more complex compounds are barely active on the cognate human {N}7-{MT}ase and docking experiments reveal that their selectivity of inhibition might result from the positioning of their {C}7 substitution in a {SAM} entry tunnel present in the nsp14 structure and absent in the h{N}7-{MT}ase. {T}hese compounds show moderate antiviral activity against {SARS}-{C}o{V}-2 replication in cell culture, suggesting delivery or stability issue.},
  keywords = {7-deaza-adenine ; {A}rylsulfonamide ; {B}isubstrate ; {SARS}-{C}o{V}-2 ; {RNA} cap ; {M}ethyltransferase ; {S}tructure -guided design},
  booktitle = {},
  journal = {{E}uropean {J}ournal of {M}edicinal {C}hemistry},
  volume = {256},
  numero = {},
  pages = {115474 [19 p.]},
  ISSN = {0223-5234},
  year = {2023},
  DOI = {10.1016/j.ejmech.2023.115474},
  URL = {https://www.documentation.ird.fr/hor/fdi:010088101},
}