How to overcome resistance of influenza A viruses against adamantane derivatives
Identifieur interne : 001B04 ( Main/Exploration ); précédent : 001B03; suivant : 001B05How to overcome resistance of influenza A viruses against adamantane derivatives
Auteurs : C. Scholtissek [États-Unis] ; G. Quack [Allemagne] ; H. D Klenk [Allemagne] ; R. G Webster [États-Unis]Source :
- Antiviral Research [ 0166-3542 ] ; 1998.
Descripteurs français
- KwdFr :
- Adamantane (), Adamantane (analogues et dérivés), Animaux, Antiviraux (pharmacologie), Chiens, Concentration en ions d'hydrogène, Embryon de poulet, Glycoprotéine hémagglutinine du virus influenza (génétique), Humains, Hémolyse, Lignée cellulaire, Protéines de la matrice virale (génétique), Réplication virale, Résistance microbienne aux médicaments, Structure moléculaire, Variation génétique, Virus de la grippe A (), Virus de la grippe A (génétique), Virus de la grippe A (physiologie).
- MESH :
- analogues et dérivés : Adamantane.
- génétique : Glycoprotéine hémagglutinine du virus influenza, Protéines de la matrice virale, Virus de la grippe A.
- pharmacologie : Antiviraux.
- physiologie : Virus de la grippe A.
- Pascal (Inist)
- Adamantane, Adamantane dérivé, Amantadine, Animaux, Antiviral, Canal ionique, Chiens, Concentration en ions d'hydrogène, Embryon de poulet, Humains, Hémagglutinine, Hémolyse, Influenzavirus A, Lignée cellulaire, Mémantine, Protéine M2, Relation structure activité, Réplication virale, Résistance, Résistance microbienne aux médicaments, Réversion, Structure moléculaire, Variation génétique, Virus de la grippe A.
English descriptors
- KwdEn :
- Adamantane (analogs & derivatives), Adamantane (chemistry), Amantadine, Animals, Antiviral, Antiviral Agents (pharmacology), Cell Line, Chick Embryo, Dogs, Drug Resistance, Microbial, Genetic Variation, Hemagglutinin, Hemagglutinin Glycoproteins, Influenza Virus (genetics), Hemolysis, Humans, Hydrogen-Ion Concentration, Influenza A virus (drug effects), Influenza A virus (genetics), Influenza A virus (physiology), Influenzavirus A, Ionic channel, Memantine, Molecular Structure, Resistance, Reversion, Structure activity relation, Viral Matrix Proteins (genetics), Virus Replication.
- MESH :
- chemical , analogs & derivatives : Adamantane.
- chemical , chemistry : Adamantane.
- chemical , genetics : Hemagglutinin Glycoproteins, Influenza Virus, Viral Matrix Proteins.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Influenza A virus.
- genetics : Influenza A virus.
- physiology : Influenza A virus.
- Animals, Cell Line, Chick Embryo, Dogs, Drug Resistance, Microbial, Genetic Variation, Hemolysis, Humans, Hydrogen-Ion Concentration, Molecular Structure, Virus Replication.
- Teeft :
- Adamantane, Adamantane derivatives, Amantadine, Amantadine derivatives, Amino, Amino acid replacement, Amino acid replacements, Amino group, Anti6iral, Anti6iral research, Antiviral, Antiviral activity, Appleyard, Channel activity, Channel function, Channel region, Chicken erythrocytes, Compound, Derivative, Erythrocyte, Hemagglutinin, High concentrations, Memantine, Methyl group, Mutant, Mutation, Plaque, Plaque formation, Replication, Resistant variants, Ring system, Same concentration, Scholtissek, Side groups, Variant, Virus replication.
Abstract
Abstract: We tested two approaches to overcoming resistance of influenza A viruses against adamantane derivatives. First, adamantane derivatives that interfere with the ion channel function of the variant M2 protein of amantadine-resistant viruses may prevent drug resistance, if they are used in mixture with amantadine. Second, amantadine acts on the M2 protein (at low concentrations) and indirectly on the hemagglutinin (at concentrations at least 100 times higher). Identifying and using a drug that reacted with both targets at the same concentration might reduce development of resistance, since, in this case, two mutations, one in each target protein would be necessary at once. Such a double mutation is assumed to be a rare event. We evaluated forty adamantane derivatives and two related compounds to determine whether they interfered with plaque formation by influenza A strains, including A/Singapore/1/57 (H2N2). Variants resistant to drugs that interfered at low concentrations (≈1 μg/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 μg/ml; e.g. memantine). The former group of compounds act on the ion channel; the corresponding escape mutants tested had amino acid replacements at positions 27, 30 or 31 of the M2 protein. Hemagglutinin was the indirect target of the latter group of compounds. Variants resistant to these agents lacked amino acid replacements within the ion channel of the M2 protein and the mutants tested had amino acid replacements in the hemagglutinin. Although we failed to identify compounds that interacted with the ion channel of amantadine-resistant variants and inhibited their replication, we were able to construct at least two compounds that interfered with both the ion channel and the hemagglutinin at about the same concentration. After passage in the presence of these compounds, we either failed to obtain any drug-resistant mutants or those obtained had amino acid replacements in the ion channel of the M2 protein and the hemagglutinin.
Url:
DOI: 10.1016/S0166-3542(97)00061-2
Affiliations:
- Allemagne, États-Unis
- District de Darmstadt, District de Giessen, Hesse (Land), Tennessee
- Francfort-sur-le-Main, Marbourg
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Le document en format XML
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Scholtissek</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Quack, G" sort="Quack, G" uniqKey="Quack G" first="G" last="Quack">G. Quack</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Merz, GmbH, Eckenheimer Landstrasse 100–104, D-60318 Frankfurt</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author><author><name sortKey="Klenk, H D" sort="Klenk, H D" uniqKey="Klenk H" first="H. D" last="Klenk">H. D Klenk</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Virologie, Universität Marburg, Robert-Koch-Strasse 17, D-35037 Marburg</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Giessen</region><settlement type="city">Marbourg</settlement></placeName></affiliation></author><author><name sortKey="Webster, R G" sort="Webster, R G" uniqKey="Webster R" first="R. G" last="Webster">R. G Webster</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Antiviral Research</title><title level="j" type="abbrev">AVR</title><idno type="ISSN">0166-3542</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998">1998</date><biblScope unit="volume">37</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="83">83</biblScope><biblScope unit="page" to="95">95</biblScope></imprint><idno type="ISSN">0166-3542</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0166-3542</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adamantane (analogs & derivatives)</term><term>Adamantane (chemistry)</term><term>Amantadine</term><term>Animals</term><term>Antiviral</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Chick Embryo</term><term>Dogs</term><term>Drug Resistance, Microbial</term><term>Genetic Variation</term><term>Hemagglutinin</term><term>Hemagglutinin Glycoproteins, Influenza Virus (genetics)</term><term>Hemolysis</term><term>Humans</term><term>Hydrogen-Ion Concentration</term><term>Influenza A virus (drug effects)</term><term>Influenza A virus (genetics)</term><term>Influenza A virus (physiology)</term><term>Influenzavirus A</term><term>Ionic channel</term><term>Memantine</term><term>Molecular Structure</term><term>Resistance</term><term>Reversion</term><term>Structure activity relation</term><term>Viral Matrix Proteins (genetics)</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adamantane ()</term><term>Adamantane (analogues et dérivés)</term><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Chiens</term><term>Concentration en ions d'hydrogène</term><term>Embryon de poulet</term><term>Glycoprotéine hémagglutinine du virus influenza (génétique)</term><term>Humains</term><term>Hémolyse</term><term>Lignée cellulaire</term><term>Protéines de la matrice virale (génétique)</term><term>Réplication virale</term><term>Résistance microbienne aux médicaments</term><term>Structure moléculaire</term><term>Variation génétique</term><term>Virus de la grippe A ()</term><term>Virus de la grippe A (génétique)</term><term>Virus de la grippe A (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Adamantane</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Adamantane</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Hemagglutinin Glycoproteins, Influenza Virus</term><term>Viral Matrix Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Adamantane</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Glycoprotéine hémagglutinine du virus influenza</term><term>Protéines de la matrice virale</term><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Chick Embryo</term><term>Dogs</term><term>Drug Resistance, Microbial</term><term>Genetic Variation</term><term>Hemolysis</term><term>Humans</term><term>Hydrogen-Ion Concentration</term><term>Molecular Structure</term><term>Virus Replication</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Adamantane</term><term>Adamantane dérivé</term><term>Amantadine</term><term>Animaux</term><term>Antiviral</term><term>Canal ionique</term><term>Chiens</term><term>Concentration en ions d'hydrogène</term><term>Embryon de poulet</term><term>Humains</term><term>Hémagglutinine</term><term>Hémolyse</term><term>Influenzavirus A</term><term>Lignée cellulaire</term><term>Mémantine</term><term>Protéine M2</term><term>Relation structure activité</term><term>Réplication virale</term><term>Résistance</term><term>Résistance microbienne aux médicaments</term><term>Réversion</term><term>Structure moléculaire</term><term>Variation génétique</term><term>Virus de la grippe A</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Adamantane</term><term>Adamantane derivatives</term><term>Amantadine</term><term>Amantadine derivatives</term><term>Amino</term><term>Amino acid replacement</term><term>Amino acid replacements</term><term>Amino group</term><term>Anti6iral</term><term>Anti6iral research</term><term>Antiviral</term><term>Antiviral activity</term><term>Appleyard</term><term>Channel activity</term><term>Channel function</term><term>Channel region</term><term>Chicken erythrocytes</term><term>Compound</term><term>Derivative</term><term>Erythrocyte</term><term>Hemagglutinin</term><term>High concentrations</term><term>Memantine</term><term>Methyl group</term><term>Mutant</term><term>Mutation</term><term>Plaque</term><term>Plaque formation</term><term>Replication</term><term>Resistant variants</term><term>Ring system</term><term>Same concentration</term><term>Scholtissek</term><term>Side groups</term><term>Variant</term><term>Virus replication</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: We tested two approaches to overcoming resistance of influenza A viruses against adamantane derivatives. First, adamantane derivatives that interfere with the ion channel function of the variant M2 protein of amantadine-resistant viruses may prevent drug resistance, if they are used in mixture with amantadine. Second, amantadine acts on the M2 protein (at low concentrations) and indirectly on the hemagglutinin (at concentrations at least 100 times higher). Identifying and using a drug that reacted with both targets at the same concentration might reduce development of resistance, since, in this case, two mutations, one in each target protein would be necessary at once. Such a double mutation is assumed to be a rare event. We evaluated forty adamantane derivatives and two related compounds to determine whether they interfered with plaque formation by influenza A strains, including A/Singapore/1/57 (H2N2). Variants resistant to drugs that interfered at low concentrations (≈1 μg/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 μg/ml; e.g. memantine). The former group of compounds act on the ion channel; the corresponding escape mutants tested had amino acid replacements at positions 27, 30 or 31 of the M2 protein. Hemagglutinin was the indirect target of the latter group of compounds. Variants resistant to these agents lacked amino acid replacements within the ion channel of the M2 protein and the mutants tested had amino acid replacements in the hemagglutinin. Although we failed to identify compounds that interacted with the ion channel of amantadine-resistant variants and inhibited their replication, we were able to construct at least two compounds that interfered with both the ion channel and the hemagglutinin at about the same concentration. After passage in the presence of these compounds, we either failed to obtain any drug-resistant mutants or those obtained had amino acid replacements in the ion channel of the M2 protein and the hemagglutinin.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>États-Unis</li></country><region><li>District de Darmstadt</li><li>District de Giessen</li><li>Hesse (Land)</li><li>Tennessee</li></region><settlement><li>Francfort-sur-le-Main</li><li>Marbourg</li></settlement></list><tree><country name="États-Unis"><region name="Tennessee"><name sortKey="Scholtissek, C" sort="Scholtissek, C" uniqKey="Scholtissek C" first="C" last="Scholtissek">C. Scholtissek</name></region><name sortKey="Webster, R G" sort="Webster, R G" uniqKey="Webster R" first="R. G" last="Webster">R. G Webster</name></country><country name="Allemagne"><region name="Hesse (Land)"><name sortKey="Quack, G" sort="Quack, G" uniqKey="Quack G" first="G" last="Quack">G. Quack</name></region><name sortKey="Klenk, H D" sort="Klenk, H D" uniqKey="Klenk H" first="H. D" last="Klenk">H. D Klenk</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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