Structure-Based Design and Optimization of Onradivir-Derived PB2 Inhibitors for the Treatment of Influenza A

Influenza A remains a major seasonal public health burden. With the approval of onradivir, PB2 has emerged as an attractive antiviral target due to its unique and conserved structural features. Herein, using onradivir as the lead, we employed bioisosteric replacement strategies to design a series of derivatives for SAR studies. Compound 5B, bearing a cyano carboxamide moiety, exhibited strong antiviral activity with a superior safety index relative to onradivir, along with broad-spectrum inhibition against H1N1 and H3N2 strains. In an H1N1-infected mouse model, oral administration of 5B reduced lung viral load and ameliorated virus-induced pulmonary pathology and inflammatory responses. Remarkably, oral administration of 5B significantly improved survival (85.7% across all dose groups), outperforming onradivir at equivalent doses. Consistently, 5B exhibited favorable oral bioavailability, supporting sufficient plasma exposure. Molecular dynamics simulations revealed a highly stable complex with the PB2 cap-binding domain. These findings establish 5B as a promising preclinical candidate for influenza A.