Identification of Small Molecules that Interfere with H1N1 Influenza A Viral Replication

• Published in: ChemMedChem 2012-12, Vol.7 (12), p.2227-2235
• Main Authors: Bottini, Angel, De, Surya K., Baaten, Bas J. G., Wu, Bainan, Barile, Elisa, Soonthornvacharin, Stephen, Stebbins, John L., Bradley, Linda M., Chanda, Sumit K., Pellecchia, Maurizio
• Format: Article
• Language: English
• Subjects: Animals; antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; drug discovery; Female; Humans; influenza; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H1N1 Subtype - physiology; Influenza, Human - drug therapy; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - virology; Real-Time Polymerase Chain Reaction; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; tetrazoles; Tetrazoles - chemistry; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Ugi reaction; Virus Replication - drug effects
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200453

Successful replication of the influenza A virus requires both viral proteins and host cellular factors. In this study we used a cellular assay to screen for small molecules capable of interfering with any of such necessary viral or cellular components. We used an established reporter assay to assess influenza viral replication by monitoring the activity of co‐expressed luciferase. We screened a diverse chemical compound library, resulting in the identification of compound 7, which inhibits a novel yet elusive target. Quantitative real‐time PCR studies confirmed the dose‐dependent inhibitory activity of compound 7 in a viral replication assay. Furthermore, we showed that compound 7 is effective in rescuing high‐dose influenza infection in an in vivo mouse model. As oseltamivir‐resistant influenza strains emerge, compound 7 could be further investigated as a new and potentially suitable scaffold for the development of anti‐influenza agents that act on novel targets. Flu fighters: A series of quinolinone‐containing small molecules that inhibit influenza replication were identified in a fluorescence‐based cellular assay. Herein we report the synthesis, characterization, and preliminary SAR studies of the most potent hit, compound 7, which demonstrated the capacity to rescue high‐dose influenza infection in an animal model.