1. A Broad Anti-influenzaHybrid Small Molecule ThatPotently Disrupts the Interaction of Polymerase Acidic Protein–BasicProtein 1 (PA-PB1) Subunits.
- Author
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Serena Massari, Giulio Nannetti, Jenny Desantis, Giulia Muratore, Stefano Sabatini, Giuseppe Manfroni, Beatrice Mercorelli, Violetta Cecchetti, Giorgio Palù, Gabriele Cruciani, Arianna Loregian, Laura Goracci, and Oriana Tabarrini
- Subjects
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RNA polymerases , *PROTEIN-protein interactions , *INFLUENZA viruses , *DRUG development , *CELL-mediated cytotoxicity , *CARBONYL compounds - Abstract
Incontinuing our efforts to identify small molecules able to disruptthe interaction of the polymerase acidic protein–basic protein1 (PA–PB1) subunits of influenza virus (Flu) RNA-dependentRNA polymerase, this paper is devoted to the optimization of a dihydrotriazolopyrimidinederivative, previously identified through structure-based drug discovery.The structure modifications performed around the bicyclic core ledto the identification of compounds endowed with both the ability todisrupt PA–PB1 subunits interaction and anti-Flu activity withno cytotoxicity. Very interesting results were obtained with the hybridmolecules 36and 37, designed by mergingsome peculiar structural features known to impart PA–PB1 interactioninhibition, with compound 36that emerged as the mostpotent PA–PB1 interaction inhibitor (IC50= 1.1μM) among all the small molecules reported so far. Calculationsshowed a very favored H-bonding between the 2-amidic carbonyl of 36and Q408, which seems to justify its potent ability tointerfere with the interaction of the polymerase subunits. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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