1. Structural Investigation of Cycloheptathiophene-3-carboxamide Derivatives Targeting Influenza Virus Polymerase Assembly
- Author
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Marzia Facchini, Stefano Sabatini, Beatrice Mercorelli, Giulia Muratore, Giulio Nannetti, Giuseppe Manfroni, Oriana Tabarrini, Violetta Cecchetti, Serena Massari, Arianna Loregian, Giorgio Palù, Laura Goracci, Luca Sancineto, and Gabriele Cruciani
- Subjects
Models, Molecular ,Drug ,medicine.drug_class ,viruses ,media_common.quotation_subject ,Context (language use) ,Carboxamide ,Thiophenes ,Biology ,Antiviral Agents ,Virus ,Structure-Activity Relationship ,chemistry.chemical_compound ,RNA polymerase ,Drug Discovery ,medicine ,Structure–activity relationship ,Enzyme Inhibitors ,Polymerase ,media_common ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug resistant mutants ,Orthomyxoviridae ,RNA-Dependent RNA Polymerase ,Virology ,chemistry ,Benzamides ,biology.protein ,Molecular Medicine - Abstract
The limited number of drug classes licensed for treatment of influenza virus (Flu), together with the continuous emergence of viral variants and drug resistant mutants, highlights the urgent need to find antivirals with novel mechanisms of action. In this context, the viral RNA-dependent RNA polymerase (RdRP) subunits assembly has emerged as an attractive target. Starting from a cycloheptathiophene-3-carboxamide derivative recently identified by us for its ability to disrupt the interaction between the PA and PB1 subunits of RdRP, we have designed and synthesized a series of analogues. Their biological evaluation led to the identification of more potent protein-protein interaction inhibitors, endowed with antiviral activity that also encompassed a number of clinical isolates of FluA, including an oseltamivir-resistant strain, and FluB, without showing appreciable toxicity. From this study, the cycloheptathiophene-3-carboxamide scaffold emerged as being particularly suitable to impart anti-Flu activity.
- Published
- 2013
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