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

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

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. 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.

Citation

Scott, C., Kankanala, J., Foster, T. L., Goldhill, D. H., Bao, P., Simmons, K., …Griffin, S. (2020). Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza. PLoS Pathogens, 16(8), Article e1008716. https://doi.org/10.1371/journal.ppat.1008716

• Journal Article Type: Article
• Acceptance Date: Jul 15, 2020
• Online Publication Date: Aug 11, 2020
• Publication Date: Aug 11, 2020
• Deposit Date: Aug 16, 2020
• Publicly Available Date: Aug 18, 2020
• Journal: PLOS Pathogens
• Print ISSN: 1553-7366
• Electronic ISSN: 1553-7374
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 8
• Article Number: e1008716
• DOI: https://doi.org/10.1371/journal.ppat.1008716
• Keywords: Immunology; Genetics; Molecular Biology; Microbiology; Parasitology; Virology
• Public URL: https://nottingham-repository.worktribe.com/output/4838687
• Publisher URL: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008716