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

Scott, C.; Kankanala, J.; Foster, T. L.; Goldhill, D.; Simmons, K. J.; Pingen, M.; Bentham, M. J.; Atkins, E.; Loundras, E.-A.; Elderfield, R.; Claridge, J. K.; Thompson, J.; Stilwell, R.; Tathineni, R.; McKimmie, C. S.; Targett-Adams, P.; Schnell, J. R.; Cook, G. P.; Barclay, W. S.; Foster, R.; Griffin, S.

doi:10.1101/713636

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bioRxiv · 10.1101/713636

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

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Abstract

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.\n\nRational 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.

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Scott, C., Kankanala, J., Foster, T. L., Goldhill, D., Simmons, K. J., Pingen, M., Bentham, M. J., Atkins, E., Loundras, E.-A., Elderfield, R., Claridge, J. K., Thompson, J., Stilwell, R., Tathineni, R., McKimmie, C. S., Targett-Adams, P., Schnell, J. R., Cook, G. P., Barclay, W. S., Foster, R., Griffin, S.. 2019-07-24. Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza. https://doi.org/10.1101/713636

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