Structural highlights
Publication Abstract from PubMedNew 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 alpha-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. Destabilization of the human RED-SMU1 splicing complex as a basis for host-directed antiinfluenza strategy.,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, Crepin T, Naffakh N Proc Natl Acad Sci U S A. 2019 May 10. pii: 1901214116. doi:, 10.1073/pnas.1901214116. PMID:31076555[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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