ABSTRACT
Introduction: The emergence of drug-resistant influenza virus strains highlights the need for new antiviral therapeutics to combat future pandemic outbreaks as well as continuing seasonal cycles of influenza.
Areas covered: This review summarizes the mechanisms of current FDA-approved anti-influenza drugs and patterns of resistance to those drugs. It also discusses potential novel targets for broad-spectrum antiviral drugs and recent progress in novel drug design to overcome drug resistance in influenza.
Expert opinion: Using the available structural information about drug-binding pockets, research is currently underway to identify molecular interactions that can be exploited to generate new antiviral drugs. Despite continued efforts, antivirals targeting viral surface proteins like HA, NA, and M2, are all susceptible to developing resistance. Structural information on the internal viral polymerase complex (PB1, PB2, and PA) provides a new avenue for influenza drug discovery. Host factors, either at the initial step of viral infection or at the later step of nuclear trafficking of viral RNP complex, are being actively pursued to generate novel drugs with new modes of action, without resulting in drug resistance.
Article highlights
The emergence of NA inhibitor-resistant influenza viruses, as well as continued circulation of M2 ion channel blocker resistant mutant strains, necessitates the design of novel antivirals against both wild-type and drug-resistant viruses.
Structure-based drug design and bioisosteric replacement strategies have made progress in the design of novel antivirals.
Antivirals that target the conserved viral polymerase complex or proteins of host origin would reduce antiviral resistance.
Combinational therapy with current FDA-approved drugs and drugs acting on novel targets of viral or host origin can be used not only to treat infection by drug-resistant mutants but also to lower the chance of eliciting novel drug resistance.
Some host-targeting antivirals, along with the most conserved viral polymerases are currently in clinical trials and may provide options for tackling with drug-resistant influenza viruses
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Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.