TGF-β inhibitor SB431542 suppresses SARS-CoV-2 replication through multistep inhibition.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic highlighted the critical need for broad-spectrum antivirals with high resistance barriers. Here, we demonstrate that SB431542, a selective TGF-β receptor I (ALK5) inhibitor, exhibits potent antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through unprecedented multitargeted mechanisms. Through comprehensive in vitro, isothermal titration calorimetry, and in silico analyses, we identified that SB431542 directly binds to SARS-CoV-2 ORF3a and disrupts its canonical function in inhibiting autophagosome-lysosome fusion. This interaction restored lysosomal acidification and normalized perinuclear LAMP-1 localization, significantly impairing virion assembly as evidenced by disrupted nucleocapsid-

SUBMITTER: Verma A 

PROVIDER: S-EPMC12455996 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature