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

Autor: Dilly S; Gustave Roussy Institute, Paris Saclay University, UMR8200 CNRS , 94805 Villejuif , France., Fotso Fotso A; Aix Marseille University, INSERM, INRA, NORT, UMR 1260/1062 , 13007 Marseille , France., Lejal N; Paris Saclay University, UR 892, INRA , 78352 Jouy en Josas , France., Zedda G; Bordeaux University, ISM (CNRS-UMR 5255) , 33405 Talence , France., Chebbo M; Aix Marseille University, INSERM, INRA, NORT, UMR 1260/1062 , 13007 Marseille , France., Rahman F; Aix Marseille University, INSERM, INRA, NORT, UMR 1260/1062 , 13007 Marseille , France., Companys S; Bordeaux University, ISM (CNRS-UMR 5255) , 33405 Talence , France., Bertrand HC; Bordeaux University, ISM (CNRS-UMR 5255) , 33405 Talence , France., Vidic J; Paris Saclay University, UR 892, INRA , 78352 Jouy en Josas , France., Noiray M; Paris Sud University, Paris Saclay University, UMS IPSIT, Intermol , 92290 Châtenay-Malabry , France., Alessi MC; Aix Marseille University, INSERM, INRA, NORT, UMR 1260/1062 , 13007 Marseille , France., Tarus B; Paris Saclay University, UR 892, INRA , 78352 Jouy en Josas , France., Quideau S; Bordeaux University, ISM (CNRS-UMR 5255) , 33405 Talence , France., Riteau B; Aix Marseille University, INSERM, INRA, NORT, UMR 1260/1062 , 13007 Marseille , France., Slama-Schwok A; Gustave Roussy Institute, Paris Saclay University, UMR8200 CNRS , 94805 Villejuif , France.; Paris Saclay University, UR 892, INRA , 78352 Jouy en Josas , France.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2018 Aug 23; Vol. 61 (16), pp. 7202-7217. Date of Electronic Publication: 2018 Aug 03.
DOI: 10.1021/acs.jmedchem.8b00557
Abstrakt: 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.
Databáze: MEDLINE
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