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_name
PLoS Pathogjournal_title
PLoS pathogensauthors
Scott C,Kankanala J,Foster TL,Goldhill DH,Bao P,Simmons K,Pingen M,Bentham M,Atkins E,Loundras E,Elderfield R,Claridge JK,Thompson J,Stilwell PR,Tathineni R,McKimmie CS,Targett-Adams P,Schnell JR,Cook GP,Evans S,Bdoi
10.1371/journal.ppat.1008716subject
Has Abstractpub_date
2020-08-11 00:00:00pages
e1008716issue
8eissn
1553-7366issn
1553-7374pii
PPATHOGENS-D-19-01729journal_volume
16pub_type
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