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Robert G Webster - One of the best experts on this subject based on the ideXlab platform.
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neuraminidase inhibitor Rimantadine combinations exert additive and synergistic anti influenza virus effects in mdck cells
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Elena A Govorkova, Robert G Webster, Hongbin FangAbstract:There is insufficient information about combination therapy with approved anti-influenza agents. We tested combinations that paired a neuraminidase (NA) inhibitor (zanamivir, oseltamivir carboxylate, or peramivir) with Rimantadine against infection of MDCK cells with H1N1 and H3N2 subtypes of influenza A virus and characterized their mode of interaction. When reduction of extracellular virus was analyzed by individual regression models and three-dimensional representations of the data, all three combinations showed additive and synergistic effects with no cytotoxicity. Maximum synergy against A/New Caledonia/20/99 (H1N1) virus infection was observed with <2.5 μM Rimantadine paired with low concentrations of NA inhibitors. All combinations reduced the extracellular yield of A/Panama/2007/99 (H3N2) influenza virus synergistically. However, our findings were different for the cell-associated virus yield. At some drug concentrations, the yield of cell-associated virus was inhibited antagonistically. Therefore, the method of analysis can be a crucial factor in evaluating the interactions of drugs with different mechanisms. We hypothesize that assays based on cell-associated virus yield may underestimate the efficacies of drug combinations that include an NA inhibitor. Taken together, our results suggest that regimens that combine NA inhibitors and Rimantadine exert synergistic anti-influenza effects in vitro. These findings provide baseline information for therapeutic testing of the drug combinations in vivo.
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long term stability of the anti influenza a compounds amantadine and Rimantadine
Antiviral Research, 1998Co-Authors: Christoph Scholtissek, Robert G WebsterAbstract:Abstract Amantadine and Rimantadine hydrochloride were tested for stability after storage at different temperatures and under different conditions for extended periods of time. Both compounds were quite stable after storage for at least 25 years at ambient temperature; they both retained full antiviral activity after long-term storage or after boiling and holding at 65–85°C for several days. Thus, amantadine and Rimantadine could be synthesized in large quantities and stored for at least one generation without loss of activity in preparation for the next influenza A pandemic in humans.
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short communication long term stability of the anti influenza a compounds amantadine and Rimantadine
1998Co-Authors: Christoph Scholtissek, Robert G WebsterAbstract:Amantadine and Rimantadine hydrochloride were tested for stability after storage at different temperatures and under different conditions for extended periods of time. Both compounds were quite stable after storage for at least 25 years at ambient temperature; they both retained full antiviral activity after long-term storage or after boiling and holding at 65‐85°C for several days. Thus, amantadine and Rimantadine could be synthesized in large quantities and stored for at least one generation without loss of activity in preparation for the next influenza A pandemic in humans. © 1998 Elsevier Science B.V. All rights reserved.
Jun Wang - One of the best experts on this subject based on the ideXlab platform.
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unraveling the binding proton blockage and inhibition of influenza m2 wt and s31n by Rimantadine variants
ACS Medicinal Chemistry Letters, 2018Co-Authors: Antonios Drakopoulos, Christina Tzitzoglaki, Kelly L Mcguire, Anja Hoffmann, Athina Konstantinidi, Dimitrios Kolokouris, Kathrin Freudenberger, Johanna Hutterer, Gunter Gauglitz, Jun WangAbstract:Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here we investigate these concepts to explain binding and proton blockage of Rimantadine variants bearing progressively larger alkyl group size to influenza A virus M2 WT and M2 S31N protein proton channel. We showed that resistance of M2 S31N to Rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiololgy (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both Rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 wild type (WT). To compare the potency between the Rimantadine variants against M2 we applied approaches using different mimicry of M2, i.e., Isothermal Titration Calorimetry (ITC) and molecula...
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Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited
ACS medicinal chemistry letters, 2017Co-Authors: Antonios Drakopoulos, Jun Wang, Christina Tzitzoglaki, Anja Hoffmann, Kathrin Freudenberger, Gunter Gauglitz, Michaela Schmidtke, Antonios KolocourisAbstract:Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of Rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of Rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of Rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.
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Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited
2017Co-Authors: Antonios Drakopoulos, Jun Wang, Christina Tzitzoglaki, Anja Hoffmann, Kathrin Freudenberger, Gunter Gauglitz, Michaela Schmidtke, Antonios KolocourisAbstract:Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of Rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of Rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of Rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency
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Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers
Nature, 2010Co-Authors: Sarah D. Cady, Klaus Schmidt-rohr, Jun Wang, Cinque S. Soto, William F. Degrado, Mei HongAbstract:The antiviral drugs amantadine and Rimantadine target the M2 protein of influenza A virus, making an understanding of its structure important for the study of drug resistance. The results of a recent crystal structure of M2 differ from those of a solution NMR structure with regards to binding of these drugs, indicating a different mechanism of inhibition in each case. Here, using solid-state NMR spectroscopy, two different amantadine-binding sites are shown to exist in the phospholipid bilayers of M2. The current H1N1 strain pandemic virus is resistant to the established antiviral agents amantadine and Rimantadine, which target the M2 protein, a multifunctional membrane-spanning proton channel. The structure of this channel has been a subject of some controversy, since an X-ray crystal structure of part of the M2 channel showed electron density that corresponded to a single molecule of amantadine in the N-terminal half of the pore, whereas a solution NMR structure of a larger portion of the channel showed four Rimantadine molecules bound to the C-terminal lipid-facing surface of the helices. The matter now appears resolved with the publication of the high-resolution structure of the M2 channel in a phospholipid bilayer, determined using solid-state NMR spectroscopy. This reveals two amantadine-binding sites: a high-affinity site in the N-terminal channel lumen and a low-affinity site on the C-terminal protein surface. This work could be of value for the development of new anti-influenza drugs, an important goal since the 2009 seasonal virus is amantadine-sensitive but resistant to Tamiflu, raising the possibility that multiply resistant virus types might emerge in future. The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and Rimantadine^ 1 . Resistance to these drugs has compromised their effectiveness against many influenza strains, including pandemic H1N1. A recent crystal structure of M2(22–46) showed electron densities attributed to a single amantadine in the amino-terminal half of the pore^ 2 , indicating a physical occlusion mechanism for inhibition. However, a solution NMR structure of M2(18–60) showed four Rimantadines bound to the carboxy-terminal lipid-facing surface of the helices^ 3 , suggesting an allosteric mechanism. Here we show by solid-state NMR spectroscopy that two amantadine-binding sites exist in M2 in phospholipid bilayers. The high-affinity site, occupied by a single amantadine, is located in the N-terminal channel lumen, surrounded by residues mutated in amantadine-resistant viruses. Quantification of the protein–amantadine distances resulted in a 0.3 Å-resolution structure of the high-affinity binding site. The second, low-affinity, site was observed on the C-terminal protein surface, but only when the drug reaches high concentrations in the bilayer. The orientation and dynamics of the drug are distinct in the two sites, as shown by ^2H NMR. These results indicate that amantadine physically occludes the M2 channel, thus paving the way for developing new antiviral drugs against influenza viruses. The study demonstrates the ability of solid-state NMR to elucidate small-molecule interactions with membrane proteins and determine high-resolution structures of their complexes.
Antonios Kolocouris - One of the best experts on this subject based on the ideXlab platform.
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Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited
ACS medicinal chemistry letters, 2017Co-Authors: Antonios Drakopoulos, Jun Wang, Christina Tzitzoglaki, Anja Hoffmann, Kathrin Freudenberger, Gunter Gauglitz, Michaela Schmidtke, Antonios KolocourisAbstract:Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of Rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of Rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of Rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.
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Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited
2017Co-Authors: Antonios Drakopoulos, Jun Wang, Christina Tzitzoglaki, Anja Hoffmann, Kathrin Freudenberger, Gunter Gauglitz, Michaela Schmidtke, Antonios KolocourisAbstract:Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of Rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of Rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of Rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency
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influence of an additional 2 amino substituent of the 1 aminoethyl pharmacophore group on the potency of Rimantadine against influenza virus a
Bioorganic & Medicinal Chemistry Letters, 2007Co-Authors: Dimitrios Tataridis, Nicolas Kolocouris, George B. Foscolos, Antonios Kolocouris, George Fytas, Elizaveta Padalko, Johan Neyts, Christos Fytas, Erik De ClercqAbstract:We examined whether the incorporation of a second amino group into the 1-aminoethyl pharmacophore of Rimantadine 2 and into the piperidine pharmacophore of the heterocyclic Rimantadine 4 was compatible with anti-influenza virus A activity. The new synthetic molecules are capable of forming two hydrogen bonds within the receptor. We identified molecules 8 and 16, bearing the adamantyl and 1,2-diaminoethyl groups, which are equipotent to Rimantadine 2 bearing the adamantyl and 1-aminoethyl pharmacophore groups. Interestingly, diamino compound 16 is a 4-fold more potent inhibitor than its parent monoamino heterocyclic Rimantadine 4 propably because of additional hydrogen bonding interactions with the M2 protein receptor.
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Heterocyclic Rimantadine analogues with antiviral activity.
Bioorganic & medicinal chemistry, 2003Co-Authors: George Stamatiou, Nicolas Kolocouris, George B. Foscolos, Antonios Kolocouris, George Fytas, Elizaveta Padalko, Johan Neyts, Christophe Pannecouque, Myriam Witvrouw, Erik De ClercqAbstract:2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a-c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of Rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1.
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Are the 2-isomers of the drug Rimantadine active anti-influenza A agents?
Antiviral chemistry & chemotherapy, 2003Co-Authors: Grigoris Zoidis, Nicolas Kolocouris, George B. Foscolos, Antonios Kolocouris, George Fytas, P Karayannis, Elizaveta Padalko, Johan Neyts, Erik De ClercqAbstract:There is a lack of information in the medical chemistry literature concerning the anti-influenza A activity of the drug Rimantadine's 2-isomer (2-Rimantadine). We now present results showing that, although 2-adamantanamine (2-amantadine) 3 is only moderately active, some 2-Rimantadine analogues are effective anti-influenza A virus agents in vitro. The 2-Rimantadine analogues and their spirocyclobutane and spirocyclopentane congeners were synthesized through interesting routes. The 2-Rimantadine analogues were 2–4 times more potent than Rimantadine 2 against influenza virus A H2N2 strain; their spirocyclobutane congeners proved equally active to rimanta-dine 2. Two compounds exhibited a similar activity and one of the compounds was was fourfold more potent than Rimantadine 2 against H3N2 strain.
Antonios Drakopoulos - One of the best experts on this subject based on the ideXlab platform.
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unraveling the binding proton blockage and inhibition of influenza m2 wt and s31n by Rimantadine variants
ACS Medicinal Chemistry Letters, 2018Co-Authors: Antonios Drakopoulos, Christina Tzitzoglaki, Kelly L Mcguire, Anja Hoffmann, Athina Konstantinidi, Dimitrios Kolokouris, Kathrin Freudenberger, Johanna Hutterer, Gunter Gauglitz, Jun WangAbstract:Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here we investigate these concepts to explain binding and proton blockage of Rimantadine variants bearing progressively larger alkyl group size to influenza A virus M2 WT and M2 S31N protein proton channel. We showed that resistance of M2 S31N to Rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiololgy (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both Rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 wild type (WT). To compare the potency between the Rimantadine variants against M2 we applied approaches using different mimicry of M2, i.e., Isothermal Titration Calorimetry (ITC) and molecula...
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Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants
2018Co-Authors: Antonios Drakopoulos, Christina Tzitzoglaki, Anja Hoffmann, Athina Konstantinidi, Dimitrios Kolokouris, Kathrin Freudenberger, Johanna Hutterer, Kelly Mcguire, Gunter GauglitzAbstract:Recently, the binding kinetics of a ligand–target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of Rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to Rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both Rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the Rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics
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Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited
ACS medicinal chemistry letters, 2017Co-Authors: Antonios Drakopoulos, Jun Wang, Christina Tzitzoglaki, Anja Hoffmann, Kathrin Freudenberger, Gunter Gauglitz, Michaela Schmidtke, Antonios KolocourisAbstract:Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of Rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of Rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of Rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.
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Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited
2017Co-Authors: Antonios Drakopoulos, Jun Wang, Christina Tzitzoglaki, Anja Hoffmann, Kathrin Freudenberger, Gunter Gauglitz, Michaela Schmidtke, Antonios KolocourisAbstract:Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of Rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of Rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of Rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency
Ao Zhang - One of the best experts on this subject based on the ideXlab platform.
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ligand promoted pd ii catalyzed functionalization of unactivated c sp3 h bond regio and stereoselective synthesis of arylated Rimantadine derivatives
ACS Catalysis, 2016Co-Authors: Zhoulong Fan, Shiqi Shu, Qizheng Yao, Ao ZhangAbstract:Stereoselective functionalization of the adamantyl bridge methylene C(sp3)–H bonds is a rather appealing, yet challenging strategy due to the bulky and unactivated nature. Here we present a palladium-catalyzed C(sp3)–H arylation/hetereoarylation of the antivirus drug Rimantadine with the picolinamide moiety as the bidentate directing group and a mono-N-protected amino acid (MPAA) as the ligand. Multisubstituted Rimantadine substrates and diverse aryl/heteroaryl iodides are well tolerated, and a series of optically pure arylated Rimantadine derivatives have been synthesized in high regio- and diastereoselectivity that provides ample compound space for further pharmaceutical research.
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Ligand-Promoted Pd(II)-Catalyzed Functionalization of Unactivated C(sp3)–H Bond: Regio- and Stereoselective Synthesis of Arylated Rimantadine Derivatives
2016Co-Authors: Zhoulong Fan, Shiqi Shu, Qizheng Yao, Ao ZhangAbstract:Stereoselective functionalization of the adamantyl bridge methylene C(sp3)–H bonds is a rather appealing, yet challenging strategy due to the bulky and unactivated nature. Here we present a palladium-catalyzed C(sp3)–H arylation/hetereoarylation of the antivirus drug Rimantadine with the picolinamide moiety as the bidentate directing group and a mono-N-protected amino acid (MPAA) as the ligand. Multisubstituted Rimantadine substrates and diverse aryl/heteroaryl iodides are well tolerated, and a series of optically pure arylated Rimantadine derivatives have been synthesized in high regio- and diastereoselectivity that provides ample compound space for further pharmaceutical research
