A novel ursodeoxycholic acid derivative exhibits broad-spectrum antiviral activity against influenza A virus and coronaviruses by multiphasic disruption of the viral life cycle

ABSTRACT Seasonal influenza virus and human coronaviruses (HCoVs) represent persistent threats to global public health, with current antiviral agents limited by narrow-spectrum activity and the emergence of drug resistance. Multi-stage and multi-target antiviral agents enhance therapeutic efficacy and overcome drug resistance versus single-target therapies by inhibiting multiple key steps of the viral life cycle, such as entry, replication, and release. Here, we characterize a novel ursodeoxycholic acid (UCDA) derivative (U-BSA) as a broad-spectrum antiviral candidate effective against influenza A viruses (H1N1 and H3N2), HCoVs (including HCoV-OC43 and other pseudovirus models), and respiratory syncytial virus (RSV). In vitro, U-BSA exhibited inhibitory activity against H1N1 (half-maximal effective concentration [EC50] = 4.10 µM; selectivity index [SI] > 50), H3N2 (EC50 = 2.41 µM, SI > 40), HCoV-OC43 (EC₅₀ = 9.66 µM, SI > 20), and RSV (EC50 = 6.01 µM, SI > 12). Furthermore, U-BSA conferred significant protection in a lethal influenza infection model in vivo. Mechanistic studies demonstrated that U-BSA interferes with multiple viral life cycles: it disrupts viral attachment, inhibits entry by blocking endosomal acidification, and suppresses virion release. U-BSA rescues virus-induced membrane lipid disorder, revealing that modulation of host membrane homeostasis serves as a critical upstream mechanism underlying its multiphasic antiviral inhibition. This multi-target mode of action represents a significant advance in antiviral strategy, highlighting U-BSA as a promising candidate for developing broad-spectrum antivirals against pan-respiratory virus.