From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

The nucleoprotein
(NP) of influenza A virus (IAV) required for
IAV replication is a promising target for new antivirals. We previously
identified by in silico screening naproxen being a dual inhibitor
of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory
effects. However, the recently shown strong COX2 antiviral potential
makes COX2 inhibition undesirable. Here we designed and synthesized
two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues
of the RNA binding groove, stabilizing NP monomer without inhibiting
COX2. Derivative 2 presented improved antiviral effects
in infected cells compared to that of naproxen and afforded a total
protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating
2009-pandemic and oseltamivir-resistant H1N1 virus. This improved
antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal
interactions.