Small molecule inhibition of the mitochondrial lipid transfer protein STARD7 attenuates influenza viral replication
12 affiliations
- 1Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America
- 2Calibr, a Division of The Scripps Research Institute, La Jolla, California, United States of America
- 3Department of Medical Biosciences, University of the Western Cape, Bellville, Cape Town, South Africa
- 4Department of Chemistry, Scripps Research, San Diego, California, United States of America
- 5Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America
- 6Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- 7Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- 8Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- 9The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- 10Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- 11The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- 12Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Abstract
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. Author summary: Influenza viruses continue to cause widespread illness and pose a pandemic threat, in part because existing antiviral drugs can lose effectiveness as the virus evolves resistance. To address this challenge, we focused on therapies that target host cell processes required for viral replication, rather than viral proteins. In this study, we describe a small molecule, M4, that inhibits replication of both influenza A and B viruses by blocking a critical step in the viral life cycle. We found that M4 acts on a host protein called STARD7, which aids in the intracellular movement of lipids. When STARD7 is inhibited, the components of the influenza viral ribonucleoprotein (vRNP) complex become trapped in the nucleus, preventing the virus from completing its replication cycle. Disrupting STARD7 genetically produces the same effect, confirming that this host protein is important for influenza replication. These findings point to a previously unrecognized gating mechanism that controls assembly and nuclear export of the vRNP complex during infection.Although M4 alone showed limited activity in animals, combining it with an existing antiviral drug improved antiviral efficacy. Together, our results reveal a host pathway that influenza viruses rely on, and they support host-directed combination approaches to strengthen antiviral treatment and help counter drug resistance.
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BibTeX
@article{sharma2026small,
title = {{Small molecule inhibition of the mitochondrial lipid transfer protein STARD7 attenuates influenza viral replication}},
author = {Shipra Sharma and Oyahida Khatun and Jihaan Adonis and Shaochen You and Kevin Hartenbower and Vedita Anand Singh and Namir Shaabani and Saikat De and Emi R. Matsuo and Rachel Y. Sattler and Jonathan A. Covel and Kris M. White and Laura Martin-Sancho and Malina A. Bakowski and Dylan J. Mendonsa and Ayush Mehta and Noura S. Yassir and Steven H. Olson and Naoko Matsunaga and Adolfo García-Sastre and Michael J. Bollong and Nisar A. Farhat and Megan L. Shaw and Sumit K. Chanda},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1013914},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013914},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Small molecule inhibition of the mitochondrial lipid transfer protein STARD7 attenuates influenza viral replication
AU - Shipra Sharma
AU - Oyahida Khatun
AU - Jihaan Adonis
AU - Shaochen You
AU - Kevin Hartenbower
AU - Vedita Anand Singh
AU - Namir Shaabani
AU - Saikat De
AU - Emi R. Matsuo
AU - Rachel Y. Sattler
AU - Jonathan A. Covel
AU - Kris M. White
AU - Laura Martin-Sancho
AU - Malina A. Bakowski
AU - Dylan J. Mendonsa
AU - Ayush Mehta
AU - Noura S. Yassir
AU - Steven H. Olson
AU - Naoko Matsunaga
AU - Adolfo García-Sastre
AU - Michael J. Bollong
AU - Nisar A. Farhat
AU - Megan L. Shaw
AU - Sumit K. Chanda
PY - 2026
DA - 2026/09/11
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1013914
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013914
AB - 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. Author summary: Influenza viruses continue to cause widespread illness and pose a pandemic threat, in part because existing antiviral drugs can lose effectiveness as the virus evolves resistance. To address this challenge, we focused on therapies that target host cell processes required for viral replication, rather than viral proteins. In this study, we describe a small molecule, M4, that inhibits replication of both influenza A and B viruses by blocking a critical step in the viral life cycle. We found that M4 acts on a host protein called STARD7, which aids in the intracellular movement of lipids. When STARD7 is inhibited, the components of the influenza viral ribonucleoprotein (vRNP) complex become trapped in the nucleus, preventing the virus from completing its replication cycle. Disrupting STARD7 genetically produces the same effect, confirming that this host protein is important for influenza replication. These findings point to a previously unrecognized gating mechanism that controls assembly and nuclear export of the vRNP complex during infection.Although M4 alone showed limited activity in animals, combining it with an existing antiviral drug improved antiviral efficacy. Together, our results reveal a host pathway that influenza viruses rely on, and they support host-directed combination approaches to strengthen antiviral treatment and help counter drug resistance.
SN - 1553-7374
ER -