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.

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

“…Yet, for all the PA C ‐PB1 N interaction inhibitors reported thus far, mechanistic studies using cocrystallization or resistance selection remain to be performed to verify their antiviral mode of action and precise binding mode. This could also aid to design PA C ‐PB1 N assembly inhibitors, which establish hydrophilic besides hydrophobic interactions, thereby leading to better solubility and potentially higher antiviral potency than the current lead compounds …”

“…This could also aid to design PA C -PB1 N assembly inhibitors, which establish hydrophilic besides hydrophobic interactions, thereby leading to better solubility and potentially higher antiviral potency than the current lead compounds. 232 Another protein-protein interface that was validated with peptide inhibitors 233,234 but is as yet unexplored with small molecules, is the interaction domain between PB1 C (residues 678-757; Fig. 8C, in light green) and PB2 N (residues 1-37; in dark green).…”

H9N2 Avian Influenza Virus Protein PB1 Enhances the Immune Responses of Bone Marrow-Derived Dendritic Cells by Down-Regulating miR375

“…Previous studies have shown that PB1 serves as a core subunit to incorporate PA and PB2 into the polymerase complex by directly interacting with PA and PB2 (Hemerka et al, 2009). Recently studies also reveal that PB1 interacted with PA was an attractive target for drug treatment (Massari et al, 2016; Swale et al, 2016). …”

Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface

“…Another appealing strategy to inhibit RdRp function is to interfere with its proper assembly using PPI inhibitors. To this end, small molecule compounds targeting the PA-Cter and PB1-Nter interplay have been actively pursued since 2012 (Massari et al, 2016;Muratore et al, 2012;Yuan et al, 2016d). Intriguingly, anti-influenza agents targeting the PB1-Cter and PB2-Nter interface have never been reported yet.…”