Shipra Sharma, Oyahida Khatun, Jihaan Adonis, Shaochen You, Kevin Hartenbower, Vedita Anand Singh, Namir Shaabani, Saikat De, Emi R Matsuo, Rachel Y Sattler, Jonathan A Covel, Kris M White, Laura Martin-Sancho, Malina A Bakowski, Dylan J Mendonsa, Ayush Mehta, Noura S Yassir, Steven H Olson, Naoko Matsunaga, Adolfo García-Sastre, Michael J Bollong, Nisar A Farhat, Megan L Shaw, Sumit K Chanda
The increasing appearance of drug-resistant and zoonotic influenza strains highlights an urgent need for host-directed antivirals that offer broad-spectrum activity and a higher barrier to resistance. Here, we describe the characterization of M4, a small-molecule identified from a high-throughput screen that potently inhibits influenza A and B viruses. Mechanistic studies reveal that M4 suppresses influenza virus replication by preventing formation of export-competent viral ribonucleoprotein (vRNP) complexes in the nucleus. Chemoproteomic profiling identified the lipid transfer protein STARD7 as the primary cellular target, and genetic depletion of STARD7 phenocopies the antiviral effects of M4. Additional studies localized the M4 binding site to cysteine 302 within the lipid-binding domain of STARD7, supporting a model in which STARD7-dependent lipid transfer activity promotes efficient vRNP assembly and nuclear export. Combining M4 with baloxavir enhances antiviral efficacy in a murine infection model, providing in vivo support for a host-directed therapeutic strategy. Together, these results identify STARD7 as a metabolic checkpoint licensing vRNP nuclear export and they establish a proof of concept for therapeutic intervention with small molecule inhibitors.