The oral nucleoside analogue inhibitor VV251 effectively inhibits coinfection by respiratory syncytial virus and influenza A virus

Respiratory syncytial virus (RSV) and influenza virus are the principal contributors to respiratory tract infections worldwide. Clinical treatment of RSV or influenza A virus (IAV) is limited and may be postponed because of misdiagnosis or coinfection with multiple pathogens. Here, we described VV251, the prodrug of 4'-fluorouridine, a novel oral nucleoside analog that exhibits potent inhibitory activity against RSV laboratory strains and clinical isolates, as well as IAV, in vitro. The EC₅₀ values of VV251 against these viruses ranged from nanomolar to low micromolar. Moreover, VV251 significantly reduced the viral titer of RSV A2 or IAV PR8 in a BALB/c infection model. Importantly, we further established a simultaneous RSV/IAV coinfection model to investigate the antiviral activity of VV251. Oral administration of VV251 once daily significantly inhibited viral replication and decreased the mortality of RSV/IAV-coinfected mice. Our findings establish VV251 as a broad-spectrum drug candidate for the treatment of RSV, IAV, and RSV/IAV coinfection.IMPORTANCERespiratory syncytial virus (RSV) and influenza virus are the two predominant causative agents of acute respiratory tract infections, leading to a substantial number of hospitalizations and thousands of deaths annually. The cost of treating disease caused by infection with RSV and influenza viruses is a huge financial burden on the world. We have identified a nucleotide analog with favorable pharmacokinetic properties and antiviral activity against RSV and influenza A virus (IAV) during mono- or coinfection in a mouse model. This compound has the potential to be used for the treatment of RSV, IAV, and RAV/IAV coinfection.