TGF-β inhibitor SB431542 suppresses SARS-CoV-2 replication through multistep inhibition
The COVID-19 pandemic highlighted the urgent need for antiviral drugs with high barriers to resistance. This study reveals that SB431542, a drug previously developed to inhibit TGF-β signaling, exhibits remarkable effectiveness against SARS-CoV-2 through an unprecedented triple-mechanism approach. Unlike conventional antivirals that target a single viral component, SB431542 simultaneously disrupts viral entry, assembly, and release by binding to the viral ORF3a protein and modulating host cellular processes. Most importantly, SARS-CoV-2 failed to develop resistance against SB431542 even after 50 generations of exposure-a significant advantage over current therapeutics that quickly lose effectiveness due to viral mutations. Our findings also uncover that coronaviruses exploit both lysosomal dysfunction and programmed cell death to spread efficiently, providing new targets for therapeutic intervention. This research establishes SB431542 as a promising broad-spectrum coronavirus inhibitor and demonstrates the value of targeting host-virus interactions to overcome antiviral resistance.
Authors
- Jitender Rathee
- Ramesh Kumar Dedar (ORCID: https://orcid.org/0000-0002-4111-953X)
- Ram Kumar (ORCID: https://orcid.org/0000-0003-3963-5575)
- Assim Verma (ORCID: https://orcid.org/0009-0006-9651-3055)
- Shweta Dhanda
- Deepti Parashar (ORCID: https://orcid.org/0000-0003-2688-3684)
- Benjamin E. Mayer (ORCID: https://orcid.org/0000-0003-4995-6786)
- Nitin Khandelwal (ORCID: https://orcid.org/0000-0001-7229-4413)
- Alka Nokhwal
- Naveen Kumar (ORCID: https://orcid.org/0000-0003-3974-9409)
- Bhupendra Nath Tripathi (ORCID: https://orcid.org/0000-0001-8530-0608)
- Yogesh Chander (ORCID: https://orcid.org/0000-0001-7869-9067)
- Himanshu Kamboj (ORCID: https://orcid.org/0000-0002-2650-5563)
- Thachamvally Riyesh (ORCID: https://orcid.org/0000-0003-0526-5908)
- Gayathri Pananghat
- Garvit Kumar
- Shalini Sharma (ORCID: https://orcid.org/0000-0002-3083-1708)
- Sandeep Kumar Bejjanki
Institutions
- National Research Centre on Equines (IN)
- Indian Institute of Science Education and Research Pune (IN)
- National Board of Health (DK)
- Science and Engineering Research Board (IN)
- IMEC (BE)
- ICMR-National Institute of Virology (IN)
Publication Details
- Journal
- Journal of Virology
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1128/jvi.00529-25
- Citations
- 1
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- ICAR - National Agricultural Science Fund
- Science and Engineering Research Board