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 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.

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.

Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors

2012 ◽  
Vol 96 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Xin Zhao ◽  
Yanling Jie ◽  
Matthew R. Rosenberg ◽  
Junting Wan ◽  
Shaogao Zeng ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A ◽  
Design And Synthesis ◽  
Ion Channel Inhibitors

scholarly journals Comparing modes of delivery of a combination of ion channel inhibitors for limiting secondary degeneration following partial optic nerve transection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lillian M. Toomey ◽  
Carole A. Bartlett ◽  
Nikolas Gavriel ◽  
Terence McGonigle ◽  
Maimuna Majimbi ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ion Channel ◽  
Local Delivery ◽  
Nerve Transection ◽  
Secondary Degeneration ◽  
Injury Site ◽  
Myelin Structure ◽  
Ion Channel Inhibitors ◽  
Optic Nerve Transection ◽  
Inhibitor Combination

Abstract Injury to the central nervous system is exacerbated by secondary degeneration. Previous research has shown that a combination of orally and locally administered ion channel inhibitors following partial optic nerve injury protects the myelin sheath and preserves function in the ventral optic nerve, vulnerable to secondary degeneration. However, local administration is often not clinically appropriate. This study aimed to compare the efficacy of systemic and local delivery of the ion channel inhibitor combination of lomerizine, brilliant blue G (BBG) and YM872, which inhibits voltage-gated calcium channels, P2X7 receptors and Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors respectively. Following a partial optic nerve transection, adult female PVG rats were treated with BBG and YM872 delivered via osmotic mini pump directly to the injury site, or via intraperitoneal injection, both alongside oral administration of lomerizine. Myelin structure was preserved with both delivery modes of the ion channel inhibitor combination. However, there was no effect of treatment on inflammation, either peripherally or at the injury site, or on the density of oligodendroglial cells. Taken together, the data indicate that even at lower concentrations, the combinatorial treatment may be preserving myelin structure, and that systemic and local delivery are comparable at improving outcomes following neurotrauma.

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
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