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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.

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