Characteristics of arbidol-resistant mutants of influenza virus : Implications for the mechanism of anti-influenza action of arbidol
Identifieur interne : 001202 ( Main/Exploration ); précédent : 001201; suivant : 001203Characteristics of arbidol-resistant mutants of influenza virus : Implications for the mechanism of anti-influenza action of arbidol
Auteurs : Irina A. Leneva [Royaume-Uni, Russie] ; Rupert J. Russell [Royaume-Uni] ; Yury S. Boriskin [Russie] ; Alan J. Hay [Royaume-Uni]Source :
- Antiviral research [ 0166-3542 ] ; 2009.
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- Pascal (Inist)
English descriptors
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Abstract
The antiviral drug arbidol (ARB), which is licensed in Russia for use against influenza, is known to inhibit early membrane fusion events in influenza A and B virus replication. To investigate in more detail the target and mechanism of ARB action we generated and studied the characteristics of ARB-resistant influenza virus mutants. Observations of the ARB susceptibility of reassortants between A/Singapore/l/57(H2N2) and A/chicken/Germany/27(H7N7, "Weybridge" strain) and of mutants of the latter virus identified the virus haemagglutinin (HA) as the major determinant of ARB sensitivity. ARB-resistant mutants, selected from the most sensitive reassortant, possessed single amino acid substitutions in the HA2 subunit which caused an increase in the pH of fusion and the associated conformational change in HA. ARB was shown to stabilize the HA by causing a 0.2 pH unit reduction in the pH of the transition to the low pH form, which was specifically abrogated by the resistance mutations. Some of the resistance mutations, which reduce acid stability and would disrupt ARB-HA interactions, are located in the vicinity of a potential ARB binding site identified using the docking programme Gold. Together, the results of these investigations indicate that ARB falls within a class of inhibitor which interacts with HA to stabilize it against the low pH transition to its fusogenic state and consequently inhibit HA-mediated membrane fusion during influenza virus infection.
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Leneva</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>National Institute for Medical Research, Mill Hill</s1><s2>London NW7 1AA</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>London NW7 1AA</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Centre of Drug Chemistry, Russian Chemical and Pharmaceutical Institute</s1><s2>Moscow</s2><s3>RUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Russie</country><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Russell, Rupert J" sort="Russell, Rupert J" uniqKey="Russell R" first="Rupert J." last="Russell">Rupert J. 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Leneva</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>National Institute for Medical Research, Mill Hill</s1><s2>London NW7 1AA</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>London NW7 1AA</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Centre of Drug Chemistry, Russian Chemical and Pharmaceutical Institute</s1><s2>Moscow</s2><s3>RUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Russie</country><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Russell, Rupert J" sort="Russell, Rupert J" uniqKey="Russell R" first="Rupert J." last="Russell">Rupert J. Russell</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>School of Biology, University of St Andrews</s1><s2>Fife Ky16 9ST</s2><s3>GBR</s3><sZ>2 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Fife Ky16 9ST</wicri:noRegion></affiliation></author><author><name sortKey="Boriskin, Yury S" sort="Boriskin, Yury S" uniqKey="Boriskin Y" first="Yury S." last="Boriskin">Yury S. Boriskin</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Institute of Virology, Russian Medical Academy of Sciences</s1><s2>Moscow</s2><s3>RUS</s3><sZ>3 aut.</sZ></inist:fA14><country>Russie</country><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Hay, Alan J" sort="Hay, Alan J" uniqKey="Hay A" first="Alan J." last="Hay">Alan J. Hay</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>National Institute for Medical Research, Mill Hill</s1><s2>London NW7 1AA</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>London NW7 1AA</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Antiviral research</title><title level="j" type="abbreviated">Antivir. res.</title><idno type="ISSN">0166-3542</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antiviral research</title><title level="j" type="abbreviated">Antivir. res.</title><idno type="ISSN">0166-3542</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term><term>Arbidol</term><term>Conformation</term><term>Fusion inhibitor</term><term>Hemagglutinin</term><term>Influenzavirus</term><term>Mechanism of action</term><term>Membrane fusion</term><term>Mutation</term><term>Resistance</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Inhibiteur de fusion</term><term>Résistance</term><term>Mutation</term><term>Influenzavirus</term><term>Mécanisme action</term><term>Hémagglutinine</term><term>Conformation</term><term>Fusion membranaire</term><term>Antiviral</term><term>Arbidol</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The antiviral drug arbidol (ARB), which is licensed in Russia for use against influenza, is known to inhibit early membrane fusion events in influenza A and B virus replication. To investigate in more detail the target and mechanism of ARB action we generated and studied the characteristics of ARB-resistant influenza virus mutants. Observations of the ARB susceptibility of reassortants between A/Singapore/l/57(H2N2) and A/chicken/Germany/27(H7N7, "Weybridge" strain) and of mutants of the latter virus identified the virus haemagglutinin (HA) as the major determinant of ARB sensitivity. ARB-resistant mutants, selected from the most sensitive reassortant, possessed single amino acid substitutions in the HA2 subunit which caused an increase in the pH of fusion and the associated conformational change in HA. ARB was shown to stabilize the HA by causing a 0.2 pH unit reduction in the pH of the transition to the low pH form, which was specifically abrogated by the resistance mutations. Some of the resistance mutations, which reduce acid stability and would disrupt ARB-HA interactions, are located in the vicinity of a potential ARB binding site identified using the docking programme Gold. Together, the results of these investigations indicate that ARB falls within a class of inhibitor which interacts with HA to stabilize it against the low pH transition to its fusogenic state and consequently inhibit HA-mediated membrane fusion during influenza virus infection.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li><li>Russie</li></country><region><li>District fédéral central</li></region><settlement><li>Moscou</li></settlement></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Leneva, Irina A" sort="Leneva, Irina A" uniqKey="Leneva I" first="Irina A." last="Leneva">Irina A. Leneva</name></noRegion><name sortKey="Hay, Alan J" sort="Hay, Alan J" uniqKey="Hay A" first="Alan J." last="Hay">Alan J. Hay</name><name sortKey="Russell, Rupert J" sort="Russell, Rupert J" uniqKey="Russell R" first="Rupert J." last="Russell">Rupert J. Russell</name></country><country name="Russie"><region name="District fédéral central"><name sortKey="Leneva, Irina A" sort="Leneva, Irina A" uniqKey="Leneva I" first="Irina A." last="Leneva">Irina A. Leneva</name></region><name sortKey="Boriskin, Yury S" sort="Boriskin, Yury S" uniqKey="Boriskin Y" first="Yury S." last="Boriskin">Yury S. Boriskin</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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