In continuing our efforts to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (Flu) RNA-dependent RNA polymerase, this paper was devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified through a SBDD. 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 of 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 polymerase subunits interaction.

A Broad Anti-influenza Hybrid Small Molecule that Potently Disrupts the Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Subunits Interaction

MASSARI, SERENA;DESANTIS, JENNY;SABATINI, STEFANO;MANFRONI, GIUSEPPE;CECCHETTI, Violetta;CRUCIANI, Gabriele;GORACCI, LAURA;TABARRINI, Oriana
2015

Abstract

In continuing our efforts to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (Flu) RNA-dependent RNA polymerase, this paper was devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified through a SBDD. 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 of 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 polymerase subunits interaction.
2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1342528
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