2. Academic Validation
  3. Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

  • Molecules. 2020 Jun 24;25(12):2903. doi: 10.3390/molecules25122903.
Maggie C Duncan 1,  Pascal Amoa Onguéné 2,  Ibuki Kihara 1,  Derrick N Nebangwa 3,  Maya E Naidu 1,  David E Williams 4,  Aruna D Balgi 5,  Kerstin Andrae-Marobela 6,  Michel Roberge 5,  Raymond J Andersen 4,  Masahiro Niikura 1,  Fidele Ntie-Kang 7 8 9,  Ian Tietjen 1 10
Affiliations

Affiliations

  • 1 Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
  • 2 Department of Chemistry, University Institute of Wood Technology Mbalmayo, University of Yaoundé I, Mbalmayo, Cameroon.
  • 3 Department of Biochemistry and Molecular Biology, University of Buea, CM-00237 Buea, Cameroon.
  • 4 Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
  • 5 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • 6 Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
  • 7 Department of Chemistry, University of Buea, CM-00237 Buea, Cameroon.
  • 8 Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120 Halle, Germany.
  • 9 Institute of Botany, Technical University of Dresden, 01217 Dresden, Germany.
  • 10 The Wistar Institute, Philadelphia, PA 19104, USA.
PMID: 32599753 DOI: 10.3390/molecules25122903
Abstract

The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new Antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established Antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza Antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed Antiviral development.

Keywords

M2; antivirals; chebulagic acid; influenza A virus; natural products; viroporin.

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