1. A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Subunits
- Author
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Jenny Desantis, Beatrice Mercorelli, Arianna Loregian, Stefano Sabatini, Laura Goracci, Gabriele Cruciani, Oriana Tabarrini, Serena Massari, Giuseppe Manfroni, Giulia Muratore, Giorgio Palù, Violetta Cecchetti, and Giulio Nannetti
- Subjects
Models, Molecular ,Protein subunit ,Drug Resistance ,RNA-dependent RNA polymerase ,medicine.disease_cause ,Antiviral Agents ,Madin Darby Canine Kidney Cells ,chemistry.chemical_compound ,Structure-Activity Relationship ,Viral Proteins ,Dogs ,Oseltamivir ,Models ,RNA polymerase ,Drug Discovery ,Drug Resistance, Viral ,Influenza A virus ,medicine ,Structure–activity relationship ,Animals ,Humans ,Viral ,Polymerase ,biology ,Drug discovery ,Molecular ,virus diseases ,Triazoles ,RNA-Dependent RNA Polymerase ,Small molecule ,HEK293 Cells ,Influenza B virus ,Protein Subunits ,Pyrimidines ,RNA Replicase ,Molecular Medicine ,Biochemistry ,chemistry ,biology.protein - Abstract
In continuing our efforts to identify small molecules able to disrupt the interaction of the polymerase acidic protein–basic protein 1 (PA–PB1) subunits of influenza virus (Flu) RNA-dependent RNA polymerase, this paper is devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified through structure-based drug discovery. The structure modifications performed around the bicyclic core led to the identification of compounds endowed with both the ability to disrupt PA–PB1 subunits interaction and anti-Flu activity with no cytotoxicity. Very interesting results were obtained with the hybrid molecules 36 and 37, designed by merging some peculiar structural features known to impart PA–PB1 interaction inhibition, with compound 36 that emerged as the most potent PA–PB1 interaction inhibitor (IC50 = 1.1 μM) among all the small molecules reported so far. Calculations showed a very favored H-bonding between the 2-amidic carbonyl of 36 and Q408, which seems to justify its potent ability to interfere with the interaction of the polymerase subunits.
- Published
- 2015