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© Nadia Naffakh, Institut Pasteur
Immunofluorescence detection of influenza virus nucleoprotein in infected cells
Publication : Proceedings of the National Academy of Sciences of the United States of America

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Proceedings of the National Academy of Sciences of the United States of America - 10 May 2019

Ashraf U, Tengo L, Le Corre L, Fournier G, Busca P, McCarthy AA, Rameix-Welti MA, Gravier-Pelletier C, Ruigrok RWH, Jacob Y, Vidalain PO, Pietrancosta N, Crépin T, Naffakh N,

Link to Pubmed [PMID] – 31076555

Link to DOI – 10.1073/pnas.1901214116

Proc Natl Acad Sci U S A 2019 May; 116(22): 10968-10977

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.