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Viruses traverse the human proteome through peptide interfaces that can be biomimetically leveraged for drug discovery.

Laurène Meyniel-SchicklinJérôme AmaudrutPierre MallinjoudFabrice GuillierPhilippe E MangeotLaetitia LinesAnne Aublin-GexCaroline ScholtesClaire PunginelliStéphane JolyFlorence VasseurEvelyne ManetHenri GruffatThomas HenryFarès HalitimJean-Laurent PaparinPeter MachinRaphaël DarteilDiane SampsonIvan MikaelianLydie LaneVincent NavratilMarie-Pierre Golinelli-CohenFabiola TerziPatrice AndreVincent LotteauJacky VonderscherEric C MeldrumBenoit de Chassey
Published in: Proceedings of the National Academy of Sciences of the United States of America (2024)
We present a drug design strategy based on structural knowledge of protein-protein interfaces selected through virus-host coevolution and translated into highly potential small molecules. This approach is grounded on Vinland, the most comprehensive atlas of virus-human protein-protein interactions with annotation of interacting domains. From this inspiration, we identified small viral protein domains responsible for interaction with human proteins. These peptides form a library of new chemical entities used to screen for replication modulators of several pathogens. As a proof of concept, a peptide from a KSHV protein, identified as an inhibitor of influenza virus replication, was translated into a small molecule series with low nanomolar antiviral activity. By targeting the NEET proteins, these molecules turn out to be of therapeutic interest in a nonalcoholic steatohepatitis mouse model with kidney lesions. This study provides a biomimetic framework to design original chemistries targeting cellular proteins, with indications going far beyond infectious diseases.
Keyphrases
  • protein protein
  • small molecule
  • endothelial cells
  • induced pluripotent stem cells
  • mouse model
  • infectious diseases
  • drug discovery
  • amino acid
  • high throughput
  • cancer therapy
  • single cell
  • gram negative
  • adverse drug