The World Health Organization estimates that influenza epidemics cause approximately 3 million to 5 million cases of severe illness. What’s worse, up to 650,000 people died worldwide each year. Recently, emerge studies have characterized broadly neutralizing antibodies (bnAbs) as an effective therapeutic option for influenza virus infected patients. Because the target hemagglutinin (HA) stem, identified by bnAbs is conserved. As we all know, antibodies are generally unsuited for oral delivery. A study from Maria J. P. van Dongen, et al. selected and optimized small molecules that mimic the bnAb functionality.
Firstly, JNJ4796, the leading compound in the study, showed effective anti-virus activity. The fusion inhibitor is identified as an oral active fusion inhibitor of influenza virus, neutralizing influenza A group 1 viruses by inhibiting hemagglutinin (HA)-mediated fusion, with EC50 values of 12 nM, 66 nM, 38 nM, 22 nM, 13 nM, 449 nM and 3.24 μM for H1/Bris, H1/Cal, H1/NCa, H1/PR8, H1/SI06, H5/H97 and H5/Viet, respectively.
Furthermore, oral administration of JNJ4796 could protect mice from lethal challenge of 25 times the median lethal dose (LD50) of H1N1 A/Puerto Rico/8/1934 virus. Doses of 50 and 10 mg/kg of JNJ4796 twice daily resulted in 100% survival at day 21 in comparison to the less potent compound JNJ8897. In addition, JNJ4796 resulted in dose-dependent efficacy. The dosage of 15 and 5 mg/kg of JNJ4796 twice daily gave rise to 100% survival.
All in all, JNJ4796 provides a possibility for influenza virus therapy. The novel compound also has potential to be a promising clinical drug recapitulates the bnAb hotspot interactions.