Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza
Claire Scott, Jayakanth Kankanala, Toshana L. Foster, Daniel H. Goldhill, Peng Bao, Katie J. Simmons, Marieke Pingen, Matthew Bentham, Elizabeth Atkins, Eleni-Anna Loundras, Ruth A. Elderfield, Jolyon K. Claridge, Joseph T. Thompson, Peter Stilwell, Ranjitha Tathineni, Clive S. McKimmie, Paul Targett‐Adams, Jason R. Schnell, Graham P. Cook, Stephen D. Evans, William Barclay, Richard Foster, Stephen Griffin
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.