How to overcome resistance of influenza A viruses against adamantane derivatives
Identifieur interne : 000607 ( Istex/Corpus ); précédent : 000606; suivant : 000608How to overcome resistance of influenza A viruses against adamantane derivatives
Auteurs : C. Scholtissek ; G. Quack ; H. D Klenk ; R. G WebsterSource :
- Antiviral Research [ 0166-3542 ] ; 1998.
English descriptors
- 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
Links to Exploration step
ISTEX:74CED52569DE0700AF8FC4C87C4EE673D41DCE10Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">How to overcome resistance of influenza A viruses against adamantane derivatives</title><author><name sortKey="Scholtissek, C" sort="Scholtissek, C" uniqKey="Scholtissek C" first="C" last="Scholtissek">C. Scholtissek</name><affiliation><mods:affiliation>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</mods:affiliation></affiliation></author><author><name sortKey="Quack, G" sort="Quack, G" uniqKey="Quack G" first="G" last="Quack">G. Quack</name><affiliation><mods:affiliation>Merz, GmbH, Eckenheimer Landstrasse 100–104, D-60318 Frankfurt, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klenk, H D" sort="Klenk, H D" uniqKey="Klenk H" first="H. D" last="Klenk">H. 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Scholtissek</name><affiliation><mods:affiliation>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</mods:affiliation></affiliation></author><author><name sortKey="Quack, G" sort="Quack, G" uniqKey="Quack G" first="G" last="Quack">G. Quack</name><affiliation><mods:affiliation>Merz, GmbH, Eckenheimer Landstrasse 100–104, D-60318 Frankfurt, Germany</mods:affiliation></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><mods:affiliation>Institut für Virologie, Universität Marburg, Robert-Koch-Strasse 17, D-35037 Marburg, Germany</mods:affiliation></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><mods:affiliation>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</mods:affiliation></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="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><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>amantadine</json:string><json:string>memantine</json:string><json:string>adamantane</json:string><json:string>mutant</json:string><json:string>amino acid replacements</json:string><json:string>amino</json:string><json:string>adamantane derivatives</json:string><json:string>derivative</json:string><json:string>scholtissek</json:string><json:string>hemagglutinin</json:string><json:string>anti6iral research</json:string><json:string>anti6iral</json:string><json:string>antiviral</json:string><json:string>plaque formation</json:string><json:string>replication</json:string><json:string>high concentrations</json:string><json:string>mutation</json:string><json:string>appleyard</json:string><json:string>erythrocyte</json:string><json:string>channel activity</json:string><json:string>virus replication</json:string><json:string>channel function</json:string><json:string>amino acid replacement</json:string><json:string>antiviral activity</json:string><json:string>channel region</json:string><json:string>same concentration</json:string><json:string>variant</json:string><json:string>plaque</json:string><json:string>compound</json:string><json:string>side groups</json:string><json:string>ring system</json:string><json:string>amantadine derivatives</json:string><json:string>chicken erythrocytes</json:string><json:string>amino group</json:string><json:string>methyl group</json:string><json:string>resistant variants</json:string></teeft></keywords><author><json:item><name>C Scholtissek</name><affiliations><json:string>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</json:string></affiliations></json:item><json:item><name>G Quack</name><affiliations><json:string>Merz, GmbH, Eckenheimer Landstrasse 100–104, D-60318 Frankfurt, Germany</json:string></affiliations></json:item><json:item><name>H.D Klenk</name><affiliations><json:string>Institut für Virologie, Universität Marburg, Robert-Koch-Strasse 17, D-35037 Marburg, Germany</json:string></affiliations></json:item><json:item><name>R.G Webster</name><affiliations><json:string>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</json:string></affiliations></json:item></author><arkIstex>ark:/67375/6H6-DQ3HZZS1-P</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><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.</abstract><qualityIndicators><score>10</score><pdfWordCount>5268</pdfWordCount><pdfCharCount>32912</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>13</pdfPageCount><pdfPageSize>585 x 750 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>314</abstractWordCount><abstractCharCount>2073</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>How to overcome resistance of influenza A viruses against adamantane derivatives</title><pmid><json:string>9588841</json:string></pmid><pii><json:string>S0166-3542(97)00061-2</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>Antiviral Research</title><language><json:string>unknown</json:string></language><publicationDate>1998</publicationDate><issn><json:string>0166-3542</json:string></issn><pii><json:string>S0166-3542(00)X0036-8</json:string></pii><volume>37</volume><issue>2</issue><pages><first>83</first><last>95</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>1998</json:string></date><geogName></geogName><orgName><json:string>ALSAC</json:string><json:string>Jude Children’s Research Hospital</json:string><json:string>MJ Research, Watertown, MA</json:string><json:string>National Cancer Institute</json:string><json:string>American Lebanese Syrian Associated Charities</json:string><json:string>National Institutes of Allergy and Infectious Diseases</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Costa Mesa</json:string><json:string>Elena Govorkova</json:string><json:string>Ann Arbor</json:string><json:string>L. 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(1985)</json:string><json:string>Schroeder et al., 1994</json:string><json:string>Pinto et al., 1992</json:string><json:string>Zebedee and Lamb, 1989</json:string><json:string>Appleyard, 1977</json:string><json:string>Lin et al., 1997</json:string><json:string>Hay et al., 1985</json:string><json:string>Indulen et al., 1979b</json:string><json:string>Sugrue and Hay, 1991</json:string><json:string>Danysz et al., 1997</json:string><json:string>von Itzstein et al., 1993</json:string><json:string>C. Scholtissek et al.</json:string><json:string>Daniels et al., 1985</json:string><json:string>Sansom and Kerr, 1993</json:string><json:string>Katz et al. (1990)</json:string><json:string>Bean et al., 1980</json:string><json:string>Huang et al., 1981</json:string><json:string>Appleyard and Marber, 1975</json:string><json:string>Tu et al., 1996</json:string><json:string>Davies et al., 1964</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-DQ3HZZS1-P</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - virology</json:string><json:string>2 - pharmacology & pharmacy</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - virology</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Immunology and Microbiology</json:string><json:string>3 - Virology</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - Pharmacology</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string><json:string>4 - pharmacologie. traitements medicamenteux</json:string></inist></categories><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1016/S0166-3542(97)00061-2</json:string></doi><id>74CED52569DE0700AF8FC4C87C4EE673D41DCE10</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-DQ3HZZS1-P/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-DQ3HZZS1-P/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/6H6-DQ3HZZS1-P/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">How to overcome resistance of influenza A viruses against adamantane derivatives</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>©1998 Elsevier Science B.V.</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</p></availability><date>1998</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note type="content">Fig. 1: Structures of the adamantane derivatives and related compounds used in the present study.</note><note type="content">Fig. 2: Drug-resistant variants of A/Singapore/1/57. Besides the total yield after the passage, several individual plaques were tested for resistance to amantadine and memantine. □=resistance to amantadine only; ■=resistance to memantine only; □=resistance to both, amantadine and memantine. aGroup comprises compounds 12, 16, 23, 62, 102, 117, 177, 266 and 603; bgroup comprises compounds 169, 180, 238 and 242; cgroup comprises compounds 187, 188 and 636. The figure right of the compounds designates the number of experiments performed. The figures below the compounds’ name designate the range of concentration (μg/ml medium) investigated. The figures in brackets designate the number of passages to obtain a drug-resistant virus population.</note><note type="content">Table 1: Inhibition of plaque formation by A/Singapore/1/57 (H2N2)</note><note type="content">Table 2: Amino acid replacements within the ion channel of the M2 protein of drug-resistant variants of A/Singapore/1/57 (H2N2)</note><note type="content">Table 3: Drug-resistant variants of A/Singapore/1/57 that required an increased pH for optimal lysis of erythrocytes and that have amino acid replacements in the hemagglutinin</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">How to overcome resistance of influenza A viruses against adamantane derivatives</title><author xml:id="author-0000"><persName><forename type="first">C</forename><surname>Scholtissek</surname></persName><note type="correspondence"><p>Corresponding author.</p></note><affiliation>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</affiliation></author><author xml:id="author-0001"><persName><forename type="first">G</forename><surname>Quack</surname></persName><affiliation>Merz, GmbH, Eckenheimer Landstrasse 100–104, D-60318 Frankfurt, Germany</affiliation></author><author xml:id="author-0002"><persName><forename type="first">H.D</forename><surname>Klenk</surname></persName><affiliation>Institut für Virologie, Universität Marburg, Robert-Koch-Strasse 17, D-35037 Marburg, Germany</affiliation></author><author xml:id="author-0003"><persName><forename type="first">R.G</forename><surname>Webster</surname></persName><affiliation>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</affiliation></author><idno type="istex">74CED52569DE0700AF8FC4C87C4EE673D41DCE10</idno><idno type="ark">ark:/67375/6H6-DQ3HZZS1-P</idno><idno type="DOI">10.1016/S0166-3542(97)00061-2</idno><idno type="PII">S0166-3542(97)00061-2</idno></analytic><monogr><title level="j">Antiviral Research</title><title level="j" type="abbrev">AVR</title><idno type="pISSN">0166-3542</idno><idno type="PII">S0166-3542(00)X0036-8</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="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></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>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.</p></abstract></profileDesc><revisionDesc><change when="1998">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-DQ3HZZS1-P/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1a" NDATA="IMAGE" name="gr1a"></istex:entity><istex:entity SYSTEM="gr1b" NDATA="IMAGE" name="gr1b"></istex:entity><istex:entity SYSTEM="gr1c" NDATA="IMAGE" name="gr1c"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla" xml:lang="en"><item-info><jid>AVR</jid><aid>1089</aid><ce:pii>S0166-3542(97)00061-2</ce:pii><ce:doi>10.1016/S0166-3542(97)00061-2</ce:doi><ce:copyright year="1998" type="full-transfer">Elsevier Science B.V.</ce:copyright></item-info><head><ce:title>How to overcome resistance of influenza A viruses against adamantane derivatives</ce:title><ce:author-group><ce:author><ce:given-name>C</ce:given-name><ce:surname>Scholtissek</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref></ce:author><ce:author><ce:given-name>G</ce:given-name><ce:surname>Quack</ce:surname><ce:cross-ref refid="AFF2">b</ce:cross-ref></ce:author><ce:author><ce:given-name>H.D</ce:given-name><ce:surname>Klenk</ce:surname><ce:cross-ref refid="AFF3">c</ce:cross-ref></ce:author><ce:author><ce:given-name>R.G</ce:given-name><ce:surname>Webster</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>Merz, GmbH, Eckenheimer Landstrasse 100–104, D-60318 Frankfurt, Germany</ce:textfn></ce:affiliation><ce:affiliation id="AFF3"><ce:label>c</ce:label><ce:textfn>Institut für Virologie, Universität Marburg, Robert-Koch-Strasse 17, D-35037 Marburg, Germany</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author.</ce:text></ce:correspondence></ce:author-group><ce:date-received day="16" month="6" year="1997"></ce:date-received><ce:date-accepted day="31" month="10" year="1997"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>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 <ce:italic>μ</ce:italic>g/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 <ce:italic>μ</ce:italic>g/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.</ce:simple-para></ce:abstract-sec></ce:abstract></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>How to overcome resistance of influenza A viruses against adamantane derivatives</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>How to overcome resistance of influenza A viruses against adamantane derivatives</title></titleInfo><name type="personal"><namePart type="given">C</namePart><namePart type="family">Scholtissek</namePart><affiliation>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</affiliation><description>Corresponding author.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G</namePart><namePart type="family">Quack</namePart><affiliation>Merz, GmbH, Eckenheimer Landstrasse 100–104, D-60318 Frankfurt, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H.D</namePart><namePart type="family">Klenk</namePart><affiliation>Institut für Virologie, Universität Marburg, Robert-Koch-Strasse 17, D-35037 Marburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">R.G</namePart><namePart type="family">Webster</namePart><affiliation>Department of Virology and Molecular Biology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38101, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1998</dateIssued><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract 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.</abstract><note type="content">Fig. 1: Structures of the adamantane derivatives and related compounds used in the present study.</note><note type="content">Fig. 2: Drug-resistant variants of A/Singapore/1/57. Besides the total yield after the passage, several individual plaques were tested for resistance to amantadine and memantine. □=resistance to amantadine only; ■=resistance to memantine only; □=resistance to both, amantadine and memantine. aGroup comprises compounds 12, 16, 23, 62, 102, 117, 177, 266 and 603; bgroup comprises compounds 169, 180, 238 and 242; cgroup comprises compounds 187, 188 and 636. The figure right of the compounds designates the number of experiments performed. The figures below the compounds’ name designate the range of concentration (μg/ml medium) investigated. The figures in brackets designate the number of passages to obtain a drug-resistant virus population.</note><note type="content">Table 1: Inhibition of plaque formation by A/Singapore/1/57 (H2N2)</note><note type="content">Table 2: Amino acid replacements within the ion channel of the M2 protein of drug-resistant variants of A/Singapore/1/57 (H2N2)</note><note type="content">Table 3: Drug-resistant variants of A/Singapore/1/57 that required an increased pH for optimal lysis of erythrocytes and that have amino acid replacements in the hemagglutinin</note><relatedItem type="host"><titleInfo><title>Antiviral Research</title></titleInfo><titleInfo type="abbreviated"><title>AVR</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1998</dateIssued></originInfo><identifier type="ISSN">0166-3542</identifier><identifier type="PII">S0166-3542(00)X0036-8</identifier><part><date>1998</date><detail type="volume"><number>37</number><caption>vol.</caption></detail><detail type="issue"><number>2</number><caption>no.</caption></detail><extent unit="issue-pages"><start>67</start><end>140</end></extent><extent unit="pages"><start>83</start><end>95</end></extent></part></relatedItem><identifier type="istex">74CED52569DE0700AF8FC4C87C4EE673D41DCE10</identifier><identifier type="ark">ark:/67375/6H6-DQ3HZZS1-P</identifier><identifier type="DOI">10.1016/S0166-3542(97)00061-2</identifier><identifier type="PII">S0166-3542(97)00061-2</identifier><accessCondition type="use and reproduction" contentType="copyright">©1998 Elsevier Science B.V.</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource><recordOrigin>Elsevier Science B.V., ©1998</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-DQ3HZZS1-P/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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