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Timothy A. Cross - One of the best experts on this subject based on the ideXlab platform.
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backbone structure of the Amantadine blocked trans membrane domain m2 proton channel from influenza a virus
Biophysical Journal, 2007Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Richard Bertram, Jack R. Quine, Riqiang Fu, Conggang Li, Timothy A. CrossAbstract:Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with Amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20° and 31° tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric Amantadine-blocked M2 trans-membrane channel. The influence of Amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the Amantadine-resistant mutant, S31N, in the presence and absence of Amantadine.
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Backbone structure of the Amantadine-blocked trans-membrane domain M2 proton channel from influenza A virus
Biophysical Journal, 2007Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Rachael Bertram, Jack R. Quine, Riqiang Fu, Conggang Li, Timothy A. CrossAbstract:Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with Amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20° and 31° tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric Amantadine-blocked M2 trans-membrane channel. The influence of Amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the Amantadine-resistant mutant, S31N, in the presence and absence of Amantadine. © 2007 by the Biophysical Society.
Jun Hu - One of the best experts on this subject based on the ideXlab platform.
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backbone structure of the Amantadine blocked trans membrane domain m2 proton channel from influenza a virus
Biophysical Journal, 2007Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Richard Bertram, Jack R. Quine, Riqiang Fu, Conggang Li, Timothy A. CrossAbstract:Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with Amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20° and 31° tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric Amantadine-blocked M2 trans-membrane channel. The influence of Amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the Amantadine-resistant mutant, S31N, in the presence and absence of Amantadine.
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Backbone structure of the Amantadine-blocked trans-membrane domain M2 proton channel from influenza A virus
Biophysical Journal, 2007Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Rachael Bertram, Jack R. Quine, Riqiang Fu, Conggang Li, Timothy A. CrossAbstract:Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with Amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20° and 31° tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric Amantadine-blocked M2 trans-membrane channel. The influence of Amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the Amantadine-resistant mutant, S31N, in the presence and absence of Amantadine. © 2007 by the Biophysical Society.
Mei Hong - One of the best experts on this subject based on the ideXlab platform.
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Amantadine induced conformational and dynamical changes of the influenza m2 transmembrane proton channel
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Sarah D Cady, Mei HongAbstract:The M2 protein of influenza A virus forms a transmembrane proton channel important for viral infection and replication. Amantadine blocks this channel, thus inhibiting viral replication. Elucidating the high-resolution structure of the M2 protein and its change upon Amantadine binding is crucial for designing antiviral drugs to combat the growing resistance of influenza A viruses against Amantadine. We used magic-angle-spinning solid-state NMR to determine the conformation and dynamics of the transmembrane domain of the protein M2TMP in the apo- and Amantadine-bound states in lipid bilayers. 13C chemical shifts and torsion angles of the protein in 1,2-dilauroyl-sn-glycero-3-phosphatidylcholine (DLPC) bilayers indicate that M2TMP is α-helical in both states, but the average conformation differs subtly, especially at the G34–I35 linkage and V27 side chain. In the liquid-crystalline membrane, the complexed M2TMP shows dramatically narrower lines than the apo peptide. Analysis of the homogeneous and inhomogeneous line widths indicates that the apo-M2TMP undergoes significant microsecond-time scale motion, and Amantadine binding alters the motional rates, causing line-narrowing. Amantadine also reduces the conformational heterogeneity of specific residues, including the G34/I35 pair and several side chains. Finally, Amantadine causes the helical segment N-terminal to G34 to increase its tilt angle by 3°, and the G34–I35 torsion angles cause a kink of 5° in the Amantadine-bound helix. These data indicate that Amantadine affects the M2 proton channel mainly by changing the distribution and exchange rates among multiple low-energy conformations and only subtly alters the average conformation and orientation. Amantadine-resistant mutations thus may arise from binding-incompetent changes in the conformational equilibrium.
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Amantadine-induced conformational and dynamical changes of the influenza M2 transmembrane proton channel.
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Sarah D Cady, Mei HongAbstract:The M2 protein of influenza A virus forms a transmembrane proton channel important for viral infection and replication. Amantadine blocks this channel, thus inhibiting viral replication. Elucidating the high-resolution structure of the M2 protein and its change upon Amantadine binding is crucial for designing antiviral drugs to combat the growing resistance of influenza A viruses against Amantadine. We used magic-angle-spinning solid-state NMR to determine the conformation and dynamics of the transmembrane domain of the protein M2TMP in the apo- and Amantadine-bound states in lipid bilayers. (13)C chemical shifts and torsion angles of the protein in 1,2-dilauroyl-sn-glycero-3-phosphatidylcholine (DLPC) bilayers indicate that M2TMP is alpha-helical in both states, but the average conformation differs subtly, especially at the G34-I35 linkage and V27 side chain. In the liquid-crystalline membrane, the complexed M2TMP shows dramatically narrower lines than the apo peptide. Analysis of the homogeneous and inhomogeneous line widths indicates that the apo-M2TMP undergoes significant microsecond-time scale motion, and Amantadine binding alters the motional rates, causing line-narrowing. Amantadine also reduces the conformational heterogeneity of specific residues, including the G34/I35 pair and several side chains. Finally, Amantadine causes the helical segment N-terminal to G34 to increase its tilt angle by 3 degrees , and the G34-I35 torsion angles cause a kink of 5 degrees in the Amantadine-bound helix. These data indicate that Amantadine affects the M2 proton channel mainly by changing the distribution and exchange rates among multiple low-energy conformations and only subtly alters the average conformation and orientation. Amantadine-resistant mutations thus may arise from binding-incompetent changes in the conformational equilibrium.
D Rivetti - One of the best experts on this subject based on the ideXlab platform.
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Amantadine and rimantadine for preventing and treating influenza A in adults.
The Cochrane database of systematic reviews, 2020Co-Authors: T O Jefferson, V Demicheli, J J Deeks, D RivettiAbstract:Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. The objective of this review was to assess the effects and safety of Amantadine and rimantadine in healthy adults. We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and reference lists of articles. We also contacted manufacturers, researchers and authors. Randomised and quasi-randomised studies comparing Amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of Amantadine and/or rimantadine in healthy adults. For prevention trials the numbers of participants with clinically defined influenza, with serologically confirmed clinical influenza A and adverse effects were analysed. Analysis for treatment trials was of the mean duration of fever and adverse effects. Amantadine prevented 23% of clinical influenza cases (95% confidence interval 11% to 34%), and 63% of serologically confirmed clinical influenza A cases (95% confidence interval 42% to 76%). Amantadine reduced duration of fever by one day (95% confidence interval 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both Amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with Amantadine than rimantadine. Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine induces fewer adverse effects than Amantadine. [This abstract has been prepared centrally.]
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Amantadine and rimantadine for influenza a in adults
Cochrane Database of Systematic Reviews, 2006Co-Authors: Tom Jefferson, V Demicheli, Carlo Di Pietrantonj, D RivettiAbstract:Background Amantadine hydrochloride (Amantadine) and rimantadine hydrochloride (rimantadine) have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. This review was first published in 1999 and updated for the fourth time in April 2008. Objectives The objective of this review was to assess the efficacy, effectiveness and safety ('effects') of Amantadine and rimantadine in healthy adults. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1966 to April Week 4, 2008), EMBASE (1990 to April 2008) and reference lists of articles. Selection criteria Randomised and quasi-randomised studies comparing Amantadine and/or rimantadine with placebo, control medication or no intervention, or comparing doses or schedules of Amantadine and/or rimantadine in healthy adults. Data collection and analysis For prophylaxis (prevention) trials we analysed the numbers of participants with clinical influenza (influenza-like-illness or ILI) or with confirmed influenza A and adverse effects. Analysis for treatment trials was of the mean duration of fever, length of hospital stay and adverse effects. Main results Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.2). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prophylaxis were not statistically significant. Both Amantadine and rimantadine induced significant gastrointestinal (GI) adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with Amantadine than rimantadine. Neither drug affected the rate of viral shedding from the nose or the course of asymptomatic influenza. Authors' conclusions Amantadine and rimantadine have comparable efficacy and effectiveness in relieving or treating symptoms of influenza A in healthy adults, although rimantadine induces fewer adverse effects than Amantadine. The effectiveness of both drugs in interrupting transmission is probably low. Resistance of influenza viruses to Amantadine is a serious worldwide problem as shown by recent virological surveillances. Both drugs have adverse gastrointestinal (stomach and gut) effects, but Amantadine can also have serious effects on the nervous system. They should only be used in an emergency when all other measures fail.
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The Cochrane Library - Amantadine and rimantadine for influenza A in adults
Cochrane Database of Systematic Reviews, 2006Co-Authors: Tom Jefferson, V Demicheli, Carlo Di Pietrantonj, D RivettiAbstract:Background Amantadine hydrochloride (Amantadine) and rimantadine hydrochloride (rimantadine) have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. This review was first published in 1999 and updated for the fourth time in April 2008. Objectives The objective of this review was to assess the efficacy, effectiveness and safety ('effects') of Amantadine and rimantadine in healthy adults. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1966 to April Week 4, 2008), EMBASE (1990 to April 2008) and reference lists of articles. Selection criteria Randomised and quasi-randomised studies comparing Amantadine and/or rimantadine with placebo, control medication or no intervention, or comparing doses or schedules of Amantadine and/or rimantadine in healthy adults. Data collection and analysis For prophylaxis (prevention) trials we analysed the numbers of participants with clinical influenza (influenza-like-illness or ILI) or with confirmed influenza A and adverse effects. Analysis for treatment trials was of the mean duration of fever, length of hospital stay and adverse effects. Main results Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.2). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prophylaxis were not statistically significant. Both Amantadine and rimantadine induced significant gastrointestinal (GI) adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with Amantadine than rimantadine. Neither drug affected the rate of viral shedding from the nose or the course of asymptomatic influenza. Authors' conclusions Amantadine and rimantadine have comparable efficacy and effectiveness in relieving or treating symptoms of influenza A in healthy adults, although rimantadine induces fewer adverse effects than Amantadine. The effectiveness of both drugs in interrupting transmission is probably low. Resistance of influenza viruses to Amantadine is a serious worldwide problem as shown by recent virological surveillances. Both drugs have adverse gastrointestinal (stomach and gut) effects, but Amantadine can also have serious effects on the nervous system. They should only be used in an emergency when all other measures fail.
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Amantadine and rimantadine for preventing and treating influenza a in adults
Cochrane Database of Systematic Reviews, 2004Co-Authors: Tom Jefferson, J J Deeks, D RivettiAbstract:BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but these drugs are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. OBJECTIVES: The objective of this review was to assess the effectiveness and safety ("effects") of Amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2003), MEDLINE (January 1966 to November week 2, 2003), EMBASE (January 1990 to September 2003) and the reference lists of articles. We also contacted manufacturers, researchers and authors. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing Amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of Amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prevention trials the numbers of participants with clinical influenza (influenza-like-illness or ILI), i.e. confirmed influenza A, and adverse effects were analysed. Analysis for treatment trials included the mean duration of fever and length of hospital stay, and the number of adverse effects. MAIN RESULTS: Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both Amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with Amantadine than rimantadine. REVIEWERS' CONCLUSIONS: Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine causes fewer adverse effects than Amantadine.
Conggang Li - One of the best experts on this subject based on the ideXlab platform.
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backbone structure of the Amantadine blocked trans membrane domain m2 proton channel from influenza a virus
Biophysical Journal, 2007Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Richard Bertram, Jack R. Quine, Riqiang Fu, Conggang Li, Timothy A. CrossAbstract:Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with Amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20° and 31° tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric Amantadine-blocked M2 trans-membrane channel. The influence of Amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the Amantadine-resistant mutant, S31N, in the presence and absence of Amantadine.
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Backbone structure of the Amantadine-blocked trans-membrane domain M2 proton channel from influenza A virus
Biophysical Journal, 2007Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Rachael Bertram, Jack R. Quine, Riqiang Fu, Conggang Li, Timothy A. CrossAbstract:Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with Amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20° and 31° tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric Amantadine-blocked M2 trans-membrane channel. The influence of Amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the Amantadine-resistant mutant, S31N, in the presence and absence of Amantadine. © 2007 by the Biophysical Society.
