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Destabilization of the human RED-SMU1 splicing complex as a basis for host-directed antiinfluenza strategy.

Proc. Natl. Acad. Sci. U.S.A.2019 May 28;116(22):10968-10977. Epub 2019 May 10
Usama Ashraf 1 , Laura Tengo 2 , Laurent Le Corre 3 , Guillaume Fournier 1 , Patricia Busca 3 , Andrew A McCarthy 4 , Marie-Anne Rameix-Welti 5 , Christine Gravier-Pelletier 3 , Rob W H Ruigrok 2 , Yves Jacob 1 , Pierre-Olivier Vidalain 6 , Nicolas Pietrancosta 7 , Thibaut Crépin 8 , Nadia Naffakh 1
Usama Ashraf 1 , Laura Tengo 2 , Laurent Le Corre 3 , Guillaume Fournier 1 , Patricia Busca 3 , Andrew A McCarthy 4 , Marie-Anne Rameix-Welti 5 , Christine Gravier-Pelletier 3 , Rob W H Ruigrok 2 , Yves Jacob 1 , Pierre-Olivier Vidalain 6 , Nicolas Pietrancosta 7 , Thibaut Crépin 8 , Nadia Naffakh 1
+ et al

[No authors listed]

Author information
  • 1 Sorbonne Paris Cité, Université Paris Diderot EA302, 75015 Paris, France.
  • 2 Institut de Biologie Structurale (IBS), Université Grenoble-Alpes (UGA), Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), CNRS, 38044 Grenoble, France.
  • 3 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Equipe Synthèse Organique pour la Recherche Biomédicale, Université Paris Descartes, CNRS UMR 8601, 75006 Paris, France.
  • 4 European Molecular Biology Laboratory (EMBL) Grenoble, 38042 Grenoble, France.
  • 5 Assistance Publique-Hôpitaux de Paris, Laboratoire de Microbiologie, Hôpital Ambroise Paré, 92100 Boulogne-Billancourt, France.
  • 6 Université Paris Descartes, CNRS UMR 8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Equipe Chimie & Biologie, Modélisation et Immunologie pour la Thérapie, 75006 Paris, France.
  • 7 Université Paris Descartes, CNRS UMR 8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Equipe Chimie & Biologie, Modélisation et Immunologie pour la Thérapie, 75006 Paris, France nicolas.pietrancosta@sorbonneuniversite.fr thibaut.crepin@ibs.fr nadia.naffakh@pasteur.fr.
  • 8 Institut de Biologie Structurale (IBS), Université Grenoble-Alpes (UGA), Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), CNRS, 38044 Grenoble, France; nicolas.pietrancosta@sorbonneuniversite.fr thibaut.crepin@ibs.fr nadia.naffakh@pasteur.fr.

摘要


New therapeutic strategies targeting influenza are actively sought due to limitations in current drugs available. Host-directed therapy is an emerging concept to target host functions involved in pathogen life cycles and/or pathogenesis, rather than pathogen components themselves. From this perspective, we focused on an essential host partner of influenza viruses, the RED-SMU1 splicing complex. Here, we identified two synthetic molecules targeting an α-helix/groove interface essential for RED-SMU1 complex assembly. We solved the structure of the SMU1 N-terminal domain in complex with RED or bound to one of the molecules identified to disrupt this complex. We show that these compounds inhibiting RED-SMU1 interaction also decrease endogenous RED-SMU1 levels and inhibit viral mRNA splicing and viral multiplication, while preserving cell viability. Overall, our data demonstrate the potential of RED-SMU1 destabilizing molecules as an antiviral therapy that could be active against a wide range of influenza viruses and be less prone to drug resistance.

KEYWORDS: RED-SMU1 splicing complex, host-directed antivirals, influenza virus, splicing, structure-based drug screening