How to overcome resistance of influenza A viruses against adamantane derivatives.
Identifieur interne : 000384 ( PubMed/Corpus ); précédent : 000383; suivant : 000385How 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
- KwdEn :
- Adamantane (analogs & derivatives), Adamantane (chemistry), Animals, Antiviral Agents (pharmacology), Cell Line, Chick Embryo, Dogs, Drug Resistance, Microbial, Genetic Variation, Hemagglutinin Glycoproteins, Influenza Virus (genetics), Hemolysis, Humans, Hydrogen-Ion Concentration, Influenza A virus (drug effects), Influenza A virus (genetics), Influenza A virus (physiology), Molecular Structure, 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.
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 (approximately 1 microg/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 microg/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.
DOI: 10.1016/s0166-3542(97)00061-2
PubMed: 9588841
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pubmed:9588841Le document en format XML
<record><TEI><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><nlm:affiliation>Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Quack, G" sort="Quack, G" uniqKey="Quack G" first="G" last="Quack">G. Quack</name></author><author><name sortKey="Klenk, H D" sort="Klenk, H D" uniqKey="Klenk H" first="H D" last="Klenk">H D Klenk</name></author><author><name sortKey="Webster, R G" sort="Webster, R G" uniqKey="Webster R" first="R G" last="Webster">R G Webster</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="1998">1998</date><idno type="RBID">pubmed:9588841</idno><idno type="pmid">9588841</idno><idno type="doi">10.1016/s0166-3542(97)00061-2</idno><idno type="wicri:Area/PubMed/Corpus">000384</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000384</idno></publicationStmt><sourceDesc><biblStruct><analytic><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><nlm:affiliation>Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Quack, G" sort="Quack, G" uniqKey="Quack G" first="G" last="Quack">G. Quack</name></author><author><name sortKey="Klenk, H D" sort="Klenk, H D" uniqKey="Klenk H" first="H D" last="Klenk">H D Klenk</name></author><author><name sortKey="Webster, R G" sort="Webster, R G" uniqKey="Webster R" first="R G" last="Webster">R G Webster</name></author></analytic><series><title level="j">Antiviral research</title><idno type="ISSN">0166-3542</idno><imprint><date when="1998" type="published">1998</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adamantane (analogs & derivatives)</term><term>Adamantane (chemistry)</term><term>Animals</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 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>Molecular Structure</term><term>Viral Matrix Proteins (genetics)</term><term>Virus Replication</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="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="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></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 (approximately 1 microg/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 microg/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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">9588841</PMID><DateCompleted><Year>1998</Year><Month>06</Month><Day>25</Day></DateCompleted><DateRevised><Year>2019</Year><Month>09</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0166-3542</ISSN><JournalIssue CitedMedium="Print"><Volume>37</Volume><Issue>2</Issue><PubDate><Year>1998</Year><Month>Feb</Month></PubDate></JournalIssue><Title>Antiviral research</Title><ISOAbbreviation>Antiviral Res.</ISOAbbreviation></Journal><ArticleTitle>How to overcome resistance of influenza A viruses against adamantane derivatives.</ArticleTitle><Pagination><MedlinePgn>83-95</MedlinePgn></Pagination><Abstract><AbstractText>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 (approximately 1 microg/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 microg/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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Scholtissek</LastName><ForeName>C</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Quack</LastName><ForeName>G</ForeName><Initials>G</Initials></Author><Author ValidYN="Y"><LastName>Klenk</LastName><ForeName>H D</ForeName><Initials>HD</Initials></Author><Author ValidYN="Y"><LastName>Webster</LastName><ForeName>R G</ForeName><Initials>RG</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P30 CA-2765</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI-08831</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Antiviral Res</MedlineTA><NlmUniqueID>8109699</NlmUniqueID><ISSNLinking>0166-3542</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019267">Hemagglutinin Glycoproteins, Influenza Virus</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C031540">M-protein, influenza virus</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C488937">M2 protein, Influenza A virus</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014763">Viral Matrix Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>PJY633525U</RegistryNumber><NameOfSubstance UI="D000218">Adamantane</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000218" MajorTopicYN="N">Adamantane</DescriptorName><QualifierName UI="Q000031" MajorTopicYN="Y">analogs & derivatives</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002642" MajorTopicYN="N">Chick Embryo</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004285" MajorTopicYN="N">Dogs</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004352" MajorTopicYN="N">Drug Resistance, Microbial</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014644" MajorTopicYN="N">Genetic Variation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019267" MajorTopicYN="N">Hemagglutinin Glycoproteins, Influenza Virus</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006461" MajorTopicYN="N">Hemolysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" 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