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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

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Authors

Claire Scott

Jayakanth Kankanala

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



Contributors

Anice C. Lowen
Editor

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.

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

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