Novel antiviral drug discovery strategies to tackle drug-resistant mutants of influenza virus strains

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.

KEYWORDS:

• Influenza virus
• antiviral
• drug resistance
• antiviral target
• drug design

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

This box summarizes key points contained in the article.

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.

Additional information

Funding

The authors are supported by grants from the National Research Foundation of Korea (NRF2015R1D1A4A01016640 and 2018M3A9H4079358) and the Ministry of Agriculture, Food and Rural Affairs (MAFRA; 716002-7) of the Korean Government. They are also supported by the Samsung Research Funding Center of Samsung Electronics under project number SRFC-MA1502-05.