title: A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Subunits.
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.
authors: §Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors: Serena
authors: S
authors: Massari
authors: †Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors: Giulio
authors: G
authors: Nannetti
authors: §Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors: Jenny
authors: J
authors: Desantis
authors: †Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors: Giulia
authors: G
authors: Muratore
authors: §Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors: Stefano
authors: S
authors: Sabatini
authors: §Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors: Giuseppe
authors: G
authors: Manfroni
authors: †Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors: Beatrice
authors: B
authors: Mercorelli
authors: §Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors: Violetta
authors: V
authors: Cecchetti
authors: †Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors: Giorgio
authors: G
authors: Palù
authors: ‡Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors: Gabriele
authors: G
authors: Cruciani
authors: †Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
authors: Arianna
authors: A
authors: Loregian
authors: ‡Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
authors: Laura
authors: L
authors: Goracci
authors: §Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors: Oriana
authors: O
authors: Tabarrini
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004285:Dogs; D024882:Drug Resistance, Viral; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D053139:Oseltamivir / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C061290:PA protein, influenza viruses; D021122:Protein Subunits; D011743:Pyrimidines; D014230:Triazoles; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D053139:Oseltamivir; D012324:RNA-Dependent RNA Polymerase