Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses

Rami Musharrafieh, Chunlong Ma, Jun Wang

Research output: Contribution to journalArticle

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 and 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.

Original languageEnglish (US)
Article number105124
JournalEuropean Journal of Pharmaceutical Sciences
Volume141
DOIs
StatePublished - Jan 1 2020

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Amantadine
Influenza A virus
Drug Delivery Systems
Rimantadine
Orthomyxoviridae
Drug Resistance
Antiviral Agents
Human Influenza
Protons
Reverse Genetics
Influenza in Birds
Pandemics
Virus Diseases
Virus Replication
Disease Outbreaks
Electrodes
Viruses
Mutation
Health
Pharmaceutical Preparations

Keywords

  • Amantadine
  • Antiviral
  • Drug resistance
  • Influenza virus
  • M2
  • Proton channel

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

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title = "Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses",
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 and 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.",
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T1 - Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses

AU - Musharrafieh, Rami

AU - Ma, Chunlong

AU - Wang, Jun

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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 and 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.

AB - 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 and 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.

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KW - Antiviral

KW - Drug resistance

KW - Influenza virus

KW - M2

KW - Proton channel

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