Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | PLoS Pathogens, Vol 16, Iss 8, p e1008716 (2020) |
| Druh dokumentu: | article |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1008716 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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