title: Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Protein-Protein Interaction as a Target for Next-Generation Anti-influenza Therapeutics.
abstract: The limited therapeutic options against the influenza virus (flu) and increasing challenges in drug resistance make the search for next-generation agents imperative. In this context, heterotrimeric viral PA/PB1/PB2 RNA-dependent RNA polymerase is an attractive target for a challenging but strategic protein-protein interaction (PPI) inhibition approach. Since 2012, the inhibition of the polymerase PA-PB1 subunit interface has become an active field of research following the publication of PA-PB1 crystal structures. In this Perspective, we briefly discuss the validity of flu polymerase as a drug target and its inhibition through a PPI inhibition strategy, including a comprehensive analysis of available PA-PB1 structures. An overview of all of the reported PA-PB1 complex formation inhibitors is provided, and approaches used for identification of the inhibitors, the hit-to-lead studies, and the emerged structure-activity relationship are described. In addition to highlighting the strengths and weaknesses of all of the PA-PB1 heterodimerization inhibitors, we analyze their hypothesized binding modes and alignment with a pharmacophore model that we have developed.
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , 06123 Perugia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , 06123 Perugia, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Desantis
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , 06123 Perugia, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D006801:Humans; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D046912:Multiprotein Complexes; C061290:PA protein, influenza viruses; D010455:Peptides; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D013876:Thiophenes; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase