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

Abstract

Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis

“…Given its pivotal role in virus genome replication, the influenza virus polymerase represents an excellent antiviral drug target (9). Nucleoside analogue-type viral polymerase inhibitors are a successful drug class for diverse virus infections, yet their development for influenza has been very slow.…”

The PA Endonuclease Inhibitor RO-7 Protects Mice from Lethal Challenge with Influenza A or B Viruses

“…experimental polymerase inhibitors, such as VX-787/JNJ872 (22). To determine whether RO-7 treatment of mice inoculated with influenza virus leads to the development of PA mutations that give rise to antiviral resistance, we performed genotypic analysis of the endonuclease domain of the PA genes from influenza viruses isolated from lung homogenates obtained at 6 dpi from all experimental groups (Ϫ4, ϩ24, and ϩ48 hpi).…”

“…In recent years, the availability of high-quality structural information on the influenza virus polymerase proteins has renewed interest in developing antivirals that disrupt the critical role(s) these proteins play in virus replication (20)(21)(22). The influenza polymerase complex is a heterotrimer composed of the basic polymerases 1 and 2 (PB1 and PB2) and the acidic polymerase (PA) (23).…”

“…The PA protein contains the endonuclease activity required to cleave PB2-bound capped mRNAs and initiate viral transcription (35). The exact mechanisms of action of PA inhibitors are not precisely known, but they may include the sequestration of divalent cations in the protein's catalytic site that is necessary for enzymatic activity and/or interaction with RNA-binding residues, resulting in substrate competition (22). The influenza PA protein is highly conserved across influenza A viruses (20,(36)(37)(38).…”

“…Of these, compounds AL-794 and S-033188 have advanced to clinical trials (22,34), but no in vivo, preclinical efficacy of these PA inhibitors has been reported to date.…”