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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2019

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

Résumé

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.
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Dates et versions

hal-02160991 , version 1 (26-11-2019)

Identifiants

Citer

Usama Ashraf, Laura Tengo, Laurent Le Corre, Guillaume Fournier, Patricia Busca, et al.. Destabilization of the human RED–SMU1 splicing complex as a basis for host-directed antiinfluenza strategy. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (22), pp.10968-10977. ⟨10.1073/pnas.1901214116⟩. ⟨hal-02160991⟩
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