4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA–PB1 Protein–Protein Interaction: Structure–Activity Relationships Exploration with the Aid of Molecular Modeling

• Published in: Journal of medicinal chemistry 2016-03, Vol.59 (6), p.2688-2703
• Main Authors: Trist, Iuni M. L, Nannetti, Giulio, Tintori, Cristina, Fallacara, Anna Lucia, Deodato, Davide, Mercorelli, Beatrice, Palù, Giorgio, Wijtmans, Maikel, Gospodova, Tzveta, Edink, Ewald, Verheij, Mark, de Esch, Iwan, Viteva, Lilia, Loregian, Arianna, Botta, Maurizio
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Crystallography, X-Ray; DNA-Directed RNA Polymerases - antagonists & inhibitors; Dogs; Drug Design; HEK293 Cells; Humans; Influenza A virus - drug effects; Influenza, Human - drug therapy; Influenza, Human - virology; Madin Darby Canine Kidney Cells; Models, Molecular; Molecular Docking Simulation; Pyridines - chemical synthesis; Pyridines - pharmacology; Structure-Activity Relationship; Viral Plaque Assay; Viral Proteins - antagonists & inhibitors; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01935

Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA–PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure–activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA–PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations.