Identification of camphor derivatives as novel M2 ion channel inhibitors of influenza A virus

MedChemComm ◽  
2015 ◽  
Vol 6 (4) ◽  
pp. 727-731 ◽  
Author(s):  
Xin Zhao ◽  
Zhen-Wei Zhang ◽  
Wei Cui ◽  
Shengwei Chen ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Camphor Derivatives ◽  
Ion Channel Inhibitors

Amantadine derivatives have been the only drugs marketed as M2 inhibitors of influenza A for decades.

Protonation of Histidine and Histidine−Tryptophan Interaction in the Activation of the M2 Ion Channel from Influenza A Virus†

Biochemistry ◽  
2001 ◽  
Vol 40 (20) ◽  
pp. 6053-6060 ◽  
Author(s):  
Atsushi Okada ◽  
Takashi Miura ◽  
Hideo Takeuchi
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A

Direct Measurement of the Influenza A Virus M2 Protein Ion Channel Activity in Mammalian Cells

Virology ◽  
1994 ◽  
Vol 205 (1) ◽  
pp. 133-140 ◽  
Author(s):  
Chang Wang ◽  
Robert A. Lamb ◽  
Lawrence H. Pinto
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Direct Measurement ◽  
Mammalian Cells ◽  
Influenza A ◽  
Channel Activity ◽  
M2 Protein

scholarly journals Activation mechanism of the M2 ion channel of influenza A virus

2000 ◽  
Vol 40 (supplement) ◽  
pp. S32
Author(s):  
A. Okada ◽  
T. Miura ◽  
H. Takeuchi
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Activation Mechanism

scholarly journals Effect of Cytoplasmic Tail Truncations on the Activity of the M2 Ion Channel of Influenza A Virus

1999 ◽  
Vol 73 (12) ◽  
pp. 9695-9701 ◽  
Author(s):  
Kurt Tobler ◽  
Marie L. Kelly ◽  
Lawrence H. Pinto ◽  
Robert A. Lamb
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Transmembrane Domain ◽  
Stop Codon ◽  
Specific Inhibitor ◽  
Cytoplasmic Tail ◽  
Proton Channel ◽  
Tail Region

ABSTRACT The M2 protein of influenza A virus forms a proton channel that is required for viral replication. The M2 ion channel is a homotetramer and has a 24-residue N-terminal extracellular domain, a 19-residue transmembrane domain, and a 54-residue cytoplasmic tail. We show here that the N-terminal methionine residue is cleaved from the mature protein. Translational stop codons were introduced into the M2 cDNA at residues 46, 52, 62, 72, 77, 82, 87, and 92. The deletion mutants were designated truncx, according to the amino acid position that was changed to a stop codon. We studied the role of the cytoplasmic tail by measuring the ion channel activity (the current sensitive to the M2-specific inhibitor amantadine) of the cytoplasmic tail truncation mutants expressed in oocytes of Xenopus laevis. When their conductance was measured over time, mutants trunc72, trunc77, and trunc92 behaved comparably to wild-type M2 protein (a decrease of only 4% over 30 min). In contrast, conductance decreased by 28% for trunc82, 27% for trunc62, and 81% for trunc52 channels. Complete closure of the channel could be observed in some cells for trunc62 and trunc52 within 30 min. These data suggest that a role of the cytoplasmic tail region of the M2 ion channel is to stabilize the pore against premature closure while the ectodomain is exposed to low pH.

scholarly journals Efficacy, Mechanism and Antiviral Resistance of Neuraminidase Inhibitors and Adamantane against Avian Influenza

2019 ◽  
Vol 29 (2) ◽  
pp. 61
Author(s):  
Dyah Ayu Hewajuli ◽  
NLPI Dharmayanti
Keyword(s):  
Avian Influenza ◽  
Ion Channel ◽  
Influenza A ◽  
Influenza Infection ◽  
Antiviral Drug ◽  
Neuraminidase Inhibitor ◽  
M2 Protein ◽  
New Variant ◽  
Amantadine Resistance ◽  
Ion Channel Inhibitors

Vaccination and antiviral drug are often used to control influenza. However, the effectiveness of vaccine was impaired due to the emergence of new variant of virus strain. Antiviral drug consists of prophylactic and curative substances, namely M2 ion channel inhibitors (adamantane; amantadine and rimantadine) and neuraminidase (NA) inhibitors (NAIs; oseltamivir, zanamivir, peramivir, laninamivir). The synthesis and modification of antiviral neuraminidase (NA) inhibitors (NAIs) and adamantanes increased the antiviral effectiveness. The mechanism of the neuraminidase inhibitor is to prevent influenza infection by inhibiting the release of the virus from internal cells. Adamantane is antiviral drug that selectively inhibits the flow of H+ ions through M2 protein to prevent the uncoating virus particles getting into the endosome. The substitution of (H275Y, S247N, I223L, K150N, R292K, I222T, R152K, R118K, E119V) on NA protein caused resistance of avian influenza virus against the neuraminidase inhibitor. The combination of mutations (S247N, I223L, K150N) increased the resistance of influenza A (H5N1) virus. The diffusion of adamantane resistance varies among HA subtypes, the species of host, the period of isolation, and region. Mutations at residues of 26, 27, 30, 31 or 34 transmembrane M2 protein caused adamantane resistance. The unique substitution (V27I) of M2 protein of clade 2.3.2 H5N1 subtype isolated in Indonesia in 2016 has been contributed to the amantadine resistance. Antiviral combination of M2 ion channel inhibitors and neuraminidase (NA) inhibitors is effective treatments for the resistance.

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

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2903
Author(s):  
Maggie C. Duncan ◽  
Pascal Amoa Onguéné ◽  
Ibuki Kihara ◽  
Derrick N. Nebangwa ◽  
Maya E. Naidu ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Drug Resistant ◽  
M2 Protein ◽  
Virtual Screen ◽  
Chebulagic Acid ◽  
Virus Strains

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.

scholarly journals Identification of the functional core of the influenza A virus A/M2 proton-selective ion channel

2009 ◽  
Vol 106 (30) ◽  
pp. 12283-12288 ◽  
Author(s):  
C. Ma ◽  
A. L. Polishchuk ◽  
Y. Ohigashi ◽  
A. L. Stouffer ◽  
A. Schon ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A

scholarly journals Virtual Screen for Repurposing of Drugs for Candidate Influenza a M2 Ion-Channel Inhibitors

2019 ◽  
Vol 9 ◽  
Author(s):  
Draginja Radosevic ◽  
Milan Sencanski ◽  
Vladimir Perovic ◽  
Nevena Veljkovic ◽  
Jelena Prljic ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A ◽  
Virtual Screen ◽  
Ion Channel Inhibitors

scholarly journals Functional Studies and Modeling of Pore-Lining Residue Mutants of the Influenza A Virus M2 Ion Channel

Biochemistry ◽  
2010 ◽  
Vol 49 (4) ◽  
pp. 696-708 ◽  
Author(s):  
Victoria Balannik ◽  
Vincenzo Carnevale ◽  
Giacomo Fiorin ◽  
Benjamin G. Levine ◽  
Robert A. Lamb ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Functional Studies ◽  
Pore Lining
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