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.

Hirshfeld Surface, Molecular Docking Study, Spectroscopic Characterization and NLO Profile of 2‐Methoxy‐4,6‐Diphenylnicotinonitrile

“…Six pi‐alkyl interactions were formed between pi electrons of aromatic groups of the ligand and alkyl groups of residues ILE531, VAL539, ALA551, LEU654, ILE663, ILE663 and MET671 at values of 5.24 Å, 5.13 Å, 4.50 Å, 4.63 Å, 4.79 Å, 5.09 Å and 4.61 Å of the interaction distances. In the literature, there are the experimental and molecular docking simulations evaluation of biological activities of 4,6‐diphenylpyridine‐3‐carbonitrile derivatives . Trist et al .…”

“…In the literature, there are the experimental and molecular docking simulations evaluation of biological activities of 4,6‐diphenylpyridine‐3‐carbonitrile derivatives . Trist et al . and Tintori et al .…”

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

“…8D). This was followed by rational development of diverse lead compounds, 125,[129][130][131][132]231 some of which were used to generate a pharmacophore model for PA C -PB1 N interaction inhibitors. 130 For the recently identified inhibitor ANA-1 (Fig.…”

Efficient and regioselective one-step synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivatives

“…The PA−PB i te a tio as dete ted as described, 3c with some modifications. 19 Briefly, 96-well microtiter plates (Nuova Aptca) were coated with 400 ng of 6His--PA(239−716) for 3 h at 37 °C and then blocked with 2% BSA (Sigma) in PBS for 1 h at 37 °C. The 6His--PA(239−716) protein was expressed in E. coli strain BL21(DE3)pLysS and purified as already described.…”

“…3c After washing, 200 ng of GST-PB1(1−25), or of GST alone as a control, in the absence or the presence of test compounds at various concentrations, were incubated in serum-free DMEM O/N at room temperature as described. 19 Escherichia coli-expressed, purified GST and GST-PB1(1−25) proteins were obtained as previously described. 3c,20 After washing, the interaction between 6His--PA(239−716) and GST-PB1(1−25) was detected with a horseradish peroxidase-coupled anti-GST monoclonal antibody (GenScript) diluted 1:4,000 in PBS supplemented with 2% FBS.…”