2. Academic Validation
  3. A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Subunits

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

  • J Med Chem. 2015 May 14;58(9):3830-42. doi: 10.1021/acs.jmedchem.5b00012.
Serena Massari 1,  Giulio Nannetti 2,  Jenny Desantis 1,  Giulia Muratore 2,  Stefano Sabatini 1,  Giuseppe Manfroni 1,  Beatrice Mercorelli 2,  Violetta Cecchetti 1,  Giorgio Palù 2,  Gabriele Cruciani 3,  Arianna Loregian 2,  Laura Goracci 3,  Oriana Tabarrini 1
Affiliations

Affiliations

  • 1 §Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
  • 2 †Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
  • 3 ‡Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
PMID: 25856229 DOI: 10.1021/acs.jmedchem.5b00012
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.

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