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

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 ?-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.
Mesh Terms:
A549 Cells, Antiviral Agents, Chromosomal Proteins, Non-Histone, Cytokines, HEK293 Cells, Host-Pathogen Interactions, Humans, Molecular Docking Simulation, Orthomyxoviridae, Protein Binding, Protein Stability, RNA Splicing, RNA Splicing Factors, Spliceosomes
Proc Natl Acad Sci U S A
Date: Dec. 28, 2018
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