Host nucleolin-targeting unique peptide drugs as potent broad-spectrum anti-influenza therapies.

The persistent threat of influenza pandemics and seasonal outbreaks, coupled with rising resistance to existing antiviral drugs targeting influenza viruses, necessitates the development of new therapeutics. This study investigated the antiviral potential of cell-penetrating peptide-conjugated host nucleolin (NCL)-binding peptide drugs, AGM-380d (dimeric) and AGM-380t (tetrameric), as innovative, broad-spectrum host-directed anti-influenza therapies. Infection with both influenza A and B viruses (IAVs and IBVs) significantly increased NCL expression and colocalization with viral nucleoprotein (NP), a core component of viral ribonucleoprotein complexes, in both in vitro and in vivo settings. The peptide drugs rapidly localized to the nucleolus and specifically bound to NCL. This targeted binding successfully disrupted the interaction between NCL and the NP of IAV and IBV, effectively blocking nuclear NP trafficking and inhibiting the replication of both pandemic and seasonal strains. Importantly, AGM-380d and AGM-380t protected mice from lethal IAV challenge by markedly reducing lung viral replication and pathology. The combination of AGM-380t with oseltamivir resulted in 100% protection from mortality following the deadly IAV challenge. In conclusion, AGM-380d and AGM-380t are highly promising as novel, broad-spectrum host-directed antivirals for the management of seasonal and pandemic influenza.