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

Significance Influenza virus is a serious threat to global public health, and there is a critical need for innovative antiinfluenza drugs. Two broad nonexclusive approaches to inhibit viral replication are possible, either targeting viral proteins directly or targeting host proteins essential for the viral life cycle. Here, we took the second approach, which is more likely to counter the problem of drug-resistant virus emergence. Focusing on an essential host partner of influenza viruses, the RED–SMU1 splicing complex, we performed a virtual structure-based drug screening. We identified two synthetic molecules that interfere with RED–SMU1 complex assembly, inhibit the splicing of viral messenger RNAs, and show potential for the inhibition of influenza virus infections. 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.