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 Crystal Structure of the Trihydrate of the Neuraminidase Inhibitor C15H28N4O4 (Peramivir), a Potential Influenza A/B and Avian-influenza (H5N1) Drug

2007 ◽  
Vol 62 (8) ◽  
pp. 983-987 ◽  
Author(s):  
Egbert Keller ◽  
Volker Krämer
Keyword(s):  
Crystal Structure ◽  
Avian Influenza ◽  
Influenza A ◽  
Organic Molecules ◽  
Neuraminidase Inhibitor ◽  
X Rays ◽  
Water Layers ◽  
Long Time ◽  
Influenza H5n1 ◽  
Water Contents

The crystal structure of the trihydrate of peramivir (C15H28N4O4), a potential influenza A/B and avian-influenza drug, has been determined. The structure, belonging to the tetragonal space group P42212 with Z = 32, a = 27.216(4), c = 23.084(5) Å, V = 17098(5) Å3, contains four organic molecules plus 12 partially disordered water molecules per asymmetric unit. 16 Organic molecules per unit cell form a kind of 1D infinite micelle separated from vicinal micelles by approximately planar water layers. During exposure to X-rays or under long-time storage on air peramivir trihydrate undergoes a phase transition to a structurally closely related phase with reduced water contents.

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 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 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 Factors Associated With Fatality Due to Avian Influenza A(H7N9) Infection in China

2019 ◽  
Vol 71 (1) ◽  
pp. 128-132 ◽  
Author(s):  
Shufa Zheng ◽  
Qianda Zou ◽  
Xiaochen Wang ◽  
Jiaqi Bao ◽  
Fei Yu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Avian Influenza ◽  
Influenza A ◽  
Bacterial Infections ◽  
Neuraminidase Inhibitor ◽  
Inhibitor Therapy ◽  
H7n9 Virus ◽  
Factors Associated ◽  
Risk Of Death ◽  
Increased Risk

Abstract Background The high case fatality rate of influenza A(H7N9)-infected patients has been a major clinical concern. Methods To identify the common causes of death due to H7N9 as well as identify risk factors associated with the high inpatient mortality, we retrospectively collected clinical treatment information from 350 hospitalized human cases of H7N9 virus in mainland China during 2013–2017, of which 109 (31.1%) had died, and systematically analyzed the patients’ clinical characteristics and risk factors for death. Results The median age at time of infection was 57 years, whereas the median age at time of death was 61 years, significantly older than those who survived. In contrast to previous studies, we found nosocomial infections comprising Acinetobacter baumannii and Klebsiella most commonly associated with secondary bacterial infections, which was likely due to the high utilization of supportive therapies, including mechanical ventilation (52.6%), extracorporeal membrane oxygenation (14%), continuous renal replacement therapy (19.1%), and artificial liver therapy (9.7%). Age, time from illness onset to antiviral therapy initiation, and secondary bacterial infection were independent risk factors for death. Age >65 years, secondary bacterial infections, and initiation of neuraminidase-inhibitor therapy after 5 days from symptom onset were associated with increased risk of death. Conclusions Death among H7N9 virus–infected patients occurred rapidly after hospital admission, especially among older patients, followed by severe hypoxemia and multisystem organ failure. Our results show that early neuraminidase-inhibitor therapy and reduction of secondary bacterial infections can help reduce mortality. Characterization of 350 hospitalized avian influenza A(H7N9)-infected patients in China shows that age >65 years, secondary bacterial infections, and initiation of neuraminidase-inhibitor therapy after 5 days from symptom onset were associated with increased risk of death.

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.

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