2. Academic Validation
  3. 4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling

4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling

  • J Med Chem. 2016 Mar 24;59(6):2688-703. doi: 10.1021/acs.jmedchem.5b01935.
Iuni M L Trist 1,  Giulio Nannetti 2,  Cristina Tintori 1,  Anna Lucia Fallacara 1,  Davide Deodato 1,  Beatrice Mercorelli 2,  Giorgio Palù 2,  Maikel Wijtmans 3,  Tzveta Gospodova 4,  Ewald Edink 3,  Mark Verheij 3,  Iwan de Esch 3,  Lilia Viteva 4,  Arianna Loregian 2,  Maurizio Botta 1 5
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro, I-53100 Siena, Italy.
  • 2 Dipartimento di Medicina Molecolare, Università degli Studi di Padova , Via A. Gabelli 63, I-35121 Padova, Italy.
  • 3 Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
  • 4 Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences , Acad. Georgy Bonchev str. BI. 9, 1113 Sofia, Bulgaria.
  • 5 Sbarro Institute for Cancer Research and Molecular Medicine, Temple University , BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States.
PMID: 26924568 DOI: 10.1021/acs.jmedchem.5b01935
Abstract

Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for Antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA-PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure-activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA-PB1 interaction and Antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations.

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