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Eur J Pharm Sci. 2019 Oct 26:105124. doi: 10.1016/j.ejps.2019.105124. [Epub ahead of print] Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.
Musharrafieh R1, Ma C1, Wang J2.
Author information
1 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, USA. 2 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, USA. Electronic address: junwang@pharmacy.arizona.edu.
Abstract
Influenza virus infections are a persistent threat to human health due to seasonal outbreaks and sporadic pandemics. Amantadine and rimantadine are FDA-approved influenza antiviral drugs and work by inhibiting the viral M2 proton channel. However, the therapeutic potential for the antiviral amantadine/rimantadine was curtailed by the emergence of drug-resistant mutations in its target protein M2. In this study, we identified four amantadine-resistant M2 mutants among avian and human influenza A H5N1 strains circulating between 2002 to 2019: the single S31N and V27A mutants, and the S31N/L26I and S31N/V27A double mutants. Herein, utilizing two-electrode voltage clamp (TEVC) assays, we screened a panel of structurally diverse M2 inhibitors against these single and double mutant channels. Three compounds 6, 7, and 15 were found to significantly block all three M2 mutants: M2-S31N, M2-S31N/L26I, and M2-S31N/V27A. Using recombinant viruses generated from reverse genetics, we further showed that these compounds also inhibited the replication of recombinant viruses harboring either the single S31N or double S31N/L26I and S31N/V27A mutants. This work represents the first example in developing antivirals by targeting the drug-resistant double mutants of M2 proton channels.
Copyright ? 2019. Published by Elsevier B.V.
KEYWORDS:
Amantadine; Antiviral; Drug resistance; Influenza Virus; M2; Proton Channel
PMID: 31669761 DOI: 10.1016/j.ejps.2019.105124