Journal of Medicinal Chemistry · 2015 · 92 citations · 35 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryMolecular VirologyAntiviral PharmacologyAntiviral TherapyEnzyme InhibitionLigand BindingPotency OptimizationRna Polymerase StructureAntiviral Drug DesignAntiviral Structure-activity RelationshipsBondingHybrid MoleculesProtein-protein Interaction Inhibitor DiscoveryRna-dependent Rna Polymerase FunctionStructure-based Lead DiscoveryViral Polymerase Inhibitors
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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Tat-mediated delivery of heterologous proteins into cells.
Stephen E. Fawell, J Seery, Yasmin Daikh et al. · Proceedings of the National Academy of Sciences · 1994 · 1.2K citations