tetano
Editor, Senior Moderator
J Med Chem. 2016 Apr 5. [Epub ahead of print]
[h=1]Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Protein-protein Interaction as a Target for Next-generation Anti-influenza Therapeutics.[/h] Massari S, Goracci L, Desantis J, Tabarrini O.
[h=3]Abstract[/h] 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 subunits interface has become an active field of research, following the publication of PA-PB1 crystal structures. In this Perspective, the validity of flu polymerase as a drug target and its inhibition through a PPI inhibition strategy will be briefly discussed, including a comprehensive analysis of available PA-PB1 structures. An overview of all the reported PA-PB1 inhibitors will be provided; approaches used for identification of the inhibitors, the hit-to-lead studies and the emerged structure-activity relationship will be described. In addition to highlighting the strengths and weaknesses of all the PA-PB1 inhibitors, we will analyze their hypothesized binding modes and alignment with a pharmacophore model we have developed.
PMID: 27046062 [PubMed - as supplied by publisher]
[h=1]Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Protein-protein Interaction as a Target for Next-generation Anti-influenza Therapeutics.[/h] Massari S, Goracci L, Desantis J, Tabarrini O.
[h=3]Abstract[/h] 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 subunits interface has become an active field of research, following the publication of PA-PB1 crystal structures. In this Perspective, the validity of flu polymerase as a drug target and its inhibition through a PPI inhibition strategy will be briefly discussed, including a comprehensive analysis of available PA-PB1 structures. An overview of all the reported PA-PB1 inhibitors will be provided; approaches used for identification of the inhibitors, the hit-to-lead studies and the emerged structure-activity relationship will be described. In addition to highlighting the strengths and weaknesses of all the PA-PB1 inhibitors, we will analyze their hypothesized binding modes and alignment with a pharmacophore model we have developed.
PMID: 27046062 [PubMed - as supplied by publisher]