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Live Imaging and Quantification of Viral Infection in K18 hACE2 Transgenic Mice Using Reporter-Expressing Recombinant SARS-CoV-2
Published on: November 5, 2021
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TGF-β inhibitor SB431542 suppresses SARS-CoV-2 replication through multistep inhibition
Assim Verma1, Himanshu Kamboj1,2, Garvit Kumar1
1National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, India.
Journal of Virology
|August 29, 2025
Summary
SB431542, a TGF-β receptor inhibitor, shows potent broad-spectrum antiviral activity against SARS-CoV-2 by targeting viral entry, assembly, and release. Importantly, SARS-CoV-2 did not develop resistance after 50 generations, offering a significant advantage over current antivirals.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- The COVID-19 pandemic underscored the need for broad-spectrum antivirals with high resistance barriers.
- Conventional antivirals often face challenges with rapid resistance development in viruses.
Purpose of the Study:
- To investigate the antiviral potential of SB431542, a TGF-β receptor I (ALK5) inhibitor, against SARS-CoV-2.
- To elucidate the multitargeted mechanisms of SB431542 against SARS-CoV-2.
- To assess the resistance profile and in vivo efficacy of SB431542.
Main Methods:
- In vitro antiviral assays, isothermal titration calorimetry, and in silico analyses were employed.
- SARS-CoV-2 ORF3a interaction and its effect on autophagosome-lysosome fusion were studied.
- Temporal analyses of infection stages, gene expression (CLEAR network, GADD45b, BAX), and viral titers were performed.
- In vivo efficacy was tested in embryonated chicken eggs against infectious bronchitis virus (IBV).
- Sequential passaging of SARS-CoV-2 under SB431542 pressure was conducted to assess resistance development.
Main Results:
- SB431542 directly binds to SARS-CoV-2 ORF3a, disrupting lysosomal acidification and impairing virion assembly.
- The drug downregulates CLEAR network genes, restricting viral egress, and suppresses GADD45b and BAX expression, inhibiting TGF-β-induced apoptosis.
- SB431542 demonstrated potent activity with an EC50 of 751.8 nM against SARS-CoV-2 and conferred dose-dependent protection against IBV in vivo.
- No resistance variants emerged after 50 generations of SARS-CoV-2 passaging under SB431542 selection.
Conclusions:
- SB431542 is a promising broad-spectrum coronavirus inhibitor with a unique triple-mechanism approach.
- The drug targets viral entry, assembly, and release by modulating host-virus interactions, imposing high selective constraints against resistance.
- SB431542 represents a valuable therapeutic strategy for combating coronaviruses, including SARS-CoV-2, by overcoming antiviral resistance.
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