A drug that targets the host rather than the virus could get around the problem of anti-viral resistance. Every year, hundreds of thousands of people die of seasonal influenza, caused by infection with influenza A and B viruses. Influenza viruses evolve quickly, often staying one step ahead in the arms race between viruses and antiviral drugs. An alternative approach is to instead target the host, disrupting the machinery that the virus appropriates to replicate itself. Kyoung-Oh Cho and colleagues tested two drugs: AGM-380d, a dimer, and AGM-380t, a tetramer. Both drugs bind to nucleolin, a jack-of-all-trades phosphoprotein mostly found in the nucleolus, a compartment within the cell nucleus. Many viruses hijack nucleolin to complete their life cycle, using it to gain entry to cells, to replicate, and to exit the nucleus to spread further. The authors showed that in cultured cells, AGM-380d and AGM-380t trapped influenza viruses inside the nucleus, inhibiting the replication of both pandemic and seasonal flu strains. AGM-380d and AGM-380t also protected mice infected with influenza A from dying by reducing lung viral replication and pathology. The combination of AGM-380t and the antiviral drug oseltamivir (also known as Tamiflu) kept 100% of test mice alive. According to the authors, nucleolin-binding drugs are a promising avenue of research in the quest to overcome drug resistance and improve influenza management worldwide.
PNAS Nexus
Host nucleolin-targeting unique peptide drugs as potent broad-spectrum anti-influenza therapies
1-Sep-2026
J.-H.R., G.M.K., and J.I.K. are members of HLB Pep Co., Ltd, and K.-O.C. is a member of Pharmacolinx, Inc. All other authors declare that they have no competing interests.