PLoS Pathogens (Aug 2020)

Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.

  • Claire Scott,
  • Jayakanth Kankanala,
  • Toshana L Foster,
  • Daniel H Goldhill,
  • Peng Bao,
  • Katie Simmons,
  • Marieke Pingen,
  • Matthew Bentham,
  • Elizabeth Atkins,
  • Eleni Loundras,
  • Ruth Elderfield,
  • Jolyon K Claridge,
  • Joseph Thompson,
  • Peter R Stilwell,
  • Ranjitha Tathineni,
  • Clive S McKimmie,
  • Paul Targett-Adams,
  • Jason R Schnell,
  • Graham P Cook,
  • Stephen Evans,
  • Wendy S Barclay,
  • Richard Foster,
  • Stephen Griffin

DOI
https://doi.org/10.1371/journal.ppat.1008716
Journal volume & issue
Vol. 16, no. 8
p. e1008716

Abstract

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Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.