title: 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.
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.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro, I-53100 Siena, Italy.
authors.forename: Iuni M L
authors.initials: IM
authors.lastname: Trist
authors.affiliation: Dipartimento di Medicina Molecolare, Università degli Studi di Padova , Via A. Gabelli 63, I-35121 Padova, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Nannetti
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro, I-53100 Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro, I-53100 Siena, Italy.
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fallacara
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro, I-53100 Siena, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Deodato
authors.affiliation: Dipartimento di Medicina Molecolare, Università degli Studi di Padova , Via A. Gabelli 63, I-35121 Padova, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mercorelli
authors.affiliation: Dipartimento di Medicina Molecolare, Università degli Studi di Padova , Via A. Gabelli 63, I-35121 Padova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.affiliation: Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences , Acad. Georgy Bonchev str. BI. 9, 1113 Sofia, Bulgaria.
authors.forename: Tzveta
authors.initials: T
authors.lastname: Gospodova
authors.affiliation: Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ewald
authors.initials: E
authors.lastname: Edink
authors.affiliation: Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Iwan
authors.initials: I
authors.lastname: de Esch
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences , Acad. Georgy Bonchev str. BI. 9, 1113 Sofia, Bulgaria.
authors.forename: Lilia
authors.initials: L
authors.lastname: Viteva
authors.affiliation: Dipartimento di Medicina Molecolare, Università degli Studi di Padova , Via A. Gabelli 63, I-35121 Padova, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Loregian
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. Moro, I-53100 Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Temple University , BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004285:Dogs; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011725:Pyridines; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012321:DNA-Directed RNA Polymerases