AG7404 demonstrated potent antiviral activity against multiple human rhinovirus serotypes and directly inhibited hRV-B14 3C protease with an IC50 of 0.046 µM via covalent binding.
AG7404 demonstrates potent inhibition of human rhinovirus 3C proteases, providing a structural foundation for designing broad-spectrum antivirals against hRV.
Human rhinoviruses (hRVs) are major causative agents of the common cold and contribute to lower respiratory tract infections. Although extensive research efforts continue to explore potential therapeutic interventions, no clinically approved antiviral treatment currently exists for hRV infections. This study provides the structural basis of hRV 3C protease inhibition in several serotypes by AG7404, a modified rupintrivir derivative. AG7404 showed potent antiviral activity against hRV-B14, hRV-A16 and hRV-A21 with EC 50 values of 0.108, 0.191 and 0.187 µ M , respectively, and directly inhibited purified hRV-B14 3C protease with an IC 50 of 0.046 µ M . The 2.11 Å crystal structure of hRV-B14 3C protease in complex with AG7404 revealed covalent binding to the catalytic Cys146 and occupation of the substrate-binding pockets by the ligand. Comparative structural analyses incorporating ligand-free hRV-B14 3C protease structures as well as rupintrivir-bound 3C protease structures from other hRV serotypes revealed significant conformational variability of the βcII–βdII region. Molecular dynamics simulations of the structural models of hRV-A16 and hRV-A21 3C proteases showed that the binding interactions of AG7404, including critical water-mediated networks, are conserved across serotypes despite sequence variations. These findings offer structural insights into the binding mode of AG7404 and establish a foundation for the rational design of broad-spectrum antivirals targeting hRV 3C proteases.
Lee et al. (Mon,) conducted a other in Human rhinovirus infection. AG7404 was evaluated on Antiviral activity and 3C protease inhibition. AG7404 demonstrated potent antiviral activity against multiple human rhinovirus serotypes and directly inhibited hRV-B14 3C protease with an IC50 of 0.046 µM via covalent binding.