A Robust Proton Flux (pHlux) Assay for Studying the Function and Inhibition of the Influenza A M2 Proton Channel.
Identifieur interne : 000229 ( Main/Exploration ); précédent : 000228; suivant : 000230A Robust Proton Flux (pHlux) Assay for Studying the Function and Inhibition of the Influenza A M2 Proton Channel.
Auteurs : Paul Santner [Danemark] ; João Miguel Da Silva Martins [Danemark] ; Jonas S. Laursen [Danemark] ; Lars Behrendt [Danemark] ; Leise Riber [Danemark] ; Christian A. Olsen [Danemark] ; Isaiah T. Arkin [Israël] ; Jakob R. Winther [Danemark] ; Martin Willemoës [Danemark] ; Kresten Lindorff-Larsen [Danemark]Source :
- Biochemistry [ 1520-4995 ] ; 2018.
Descripteurs français
- KwdFr :
- Canaux ioniques (), Canaux ioniques (antagonistes et inhibiteurs), Canaux ioniques (métabolisme), Humains, Mutation faux-sens, Protons, Protéines de la matrice virale (), Protéines de la matrice virale (antagonistes et inhibiteurs), Protéines de la matrice virale (génétique), Protéines de la matrice virale (métabolisme), Relation structure-activité, Sous-type H2N2 du virus de la grippe A (), Sous-type H2N2 du virus de la grippe A (génétique), Sous-type H2N2 du virus de la grippe A (métabolisme), Sous-type H3N2 du virus de la grippe A (), Sous-type H3N2 du virus de la grippe A (génétique), Sous-type H3N2 du virus de la grippe A (métabolisme), Substitution d'acide aminé, Transport des ions ().
- MESH :
- antagonistes et inhibiteurs : Canaux ioniques, Protéines de la matrice virale.
- génétique : Protéines de la matrice virale, Sous-type H2N2 du virus de la grippe A, Sous-type H3N2 du virus de la grippe A.
- métabolisme : Canaux ioniques, Protéines de la matrice virale, Sous-type H2N2 du virus de la grippe A, Sous-type H3N2 du virus de la grippe A.
- Canaux ioniques, Humains, Mutation faux-sens, Protons, Protéines de la matrice virale, Relation structure-activité, Sous-type H2N2 du virus de la grippe A, Sous-type H3N2 du virus de la grippe A, Substitution d'acide aminé, Transport des ions.
English descriptors
- KwdEn :
- Amino Acid Substitution, Humans, Influenza A Virus, H2N2 Subtype (chemistry), Influenza A Virus, H2N2 Subtype (genetics), Influenza A Virus, H2N2 Subtype (metabolism), Influenza A Virus, H3N2 Subtype (chemistry), Influenza A Virus, H3N2 Subtype (genetics), Influenza A Virus, H3N2 Subtype (metabolism), Ion Channels (antagonists & inhibitors), Ion Channels (chemistry), Ion Channels (metabolism), Ion Transport (drug effects), Mutation, Missense, Protons, Structure-Activity Relationship, Viral Matrix Proteins (antagonists & inhibitors), Viral Matrix Proteins (chemistry), Viral Matrix Proteins (genetics), Viral Matrix Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Ion Channels, Viral Matrix Proteins.
- chemistry : Influenza A Virus, H2N2 Subtype, Influenza A Virus, H3N2 Subtype, Ion Channels, Viral Matrix Proteins.
- drug effects : Ion Transport.
- genetics : Influenza A Virus, H2N2 Subtype, Influenza A Virus, H3N2 Subtype, Viral Matrix Proteins.
- metabolism : Influenza A Virus, H2N2 Subtype, Influenza A Virus, H3N2 Subtype, Ion Channels, Viral Matrix Proteins.
- Amino Acid Substitution, Humans, Mutation, Missense, Protons, Structure-Activity Relationship.
Abstract
The M2 protein is an important target for drugs in the fight against the influenza virus. Because of the emergence of resistance against antivirals directed toward the M2 proton channel, the search for new drugs against resistant M2 variants is of high importance. Robust and sensitive assays for testing potential drug compounds on different M2 variants are valuable tools in this search for new inhibitors. In this work, we describe a fluorescence sensor-based assay, which we termed "pHlux", that measures proton conduction through M2 when synthesized from an expression vector in Escherichia coli. The assay was compared to a previously established bacterial potassium ion transport complementation assay, and the results were compared to simulations obtained from analysis of a computational model of M2 and its interaction with inhibitor molecules. The inhibition of M2 was measured for five different inhibitors, including Rimantadine, Amantadine, and spiro type compounds, and the drug resistance of the M2 mutant variants (swine flu, V27A, and S31N) was confirmed. We demonstrate that the pHlux assay is robust and highly sensitive and shows potential for high-throughput screening.
DOI: 10.1021/acs.biochem.8b00721
PubMed: 30230312
Affiliations:
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Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en">A Robust Proton Flux (pHlux) Assay for Studying the Function and Inhibition of the Influenza A M2 Proton Channel.</title>
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<country xml:lang="fr">Danemark</country>
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<author><name sortKey="Olsen, Christian A" sort="Olsen, Christian A" uniqKey="Olsen C" first="Christian A" last="Olsen">Christian A. Olsen</name>
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<country xml:lang="fr">Danemark</country>
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<author><name sortKey="Arkin, Isaiah T" sort="Arkin, Isaiah T" uniqKey="Arkin I" first="Isaiah T" last="Arkin">Isaiah T. Arkin</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biological Chemistry , The Hebrew University of Jerusalem , Edmond J. Safra Campus, Givat-Ram , Jerusalem 91904 , Israel.</nlm:affiliation>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>Department of Biological Chemistry , The Hebrew University of Jerusalem , Edmond J. Safra Campus, Givat-Ram , Jerusalem 91904 </wicri:regionArea>
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<author><name sortKey="Winther, Jakob R" sort="Winther, Jakob R" uniqKey="Winther J" first="Jakob R" last="Winther">Jakob R. Winther</name>
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<country xml:lang="fr">Danemark</country>
<wicri:regionArea>Department of Biology, Section for Biomolecular Sciences, Linderstrøm-Lang Centre for Protein Science , University of Copenhagen , Ole Maaloes Vej 5 , 2200 Copenhagen N</wicri:regionArea>
<wicri:noRegion>2200 Copenhagen N</wicri:noRegion>
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<author><name sortKey="Willemoes, Martin" sort="Willemoes, Martin" uniqKey="Willemoes M" first="Martin" last="Willemoës">Martin Willemoës</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biology, Section for Biomolecular Sciences, Linderstrøm-Lang Centre for Protein Science , University of Copenhagen , Ole Maaloes Vej 5 , 2200 Copenhagen N, Denmark.</nlm:affiliation>
<country xml:lang="fr">Danemark</country>
<wicri:regionArea>Department of Biology, Section for Biomolecular Sciences, Linderstrøm-Lang Centre for Protein Science , University of Copenhagen , Ole Maaloes Vej 5 , 2200 Copenhagen N</wicri:regionArea>
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<author><name sortKey="Lindorff Larsen, Kresten" sort="Lindorff Larsen, Kresten" uniqKey="Lindorff Larsen K" first="Kresten" last="Lindorff-Larsen">Kresten Lindorff-Larsen</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Biology, Section for Biomolecular Sciences, Linderstrøm-Lang Centre for Protein Science , University of Copenhagen , Ole Maaloes Vej 5 , 2200 Copenhagen N, Denmark.</nlm:affiliation>
<country xml:lang="fr">Danemark</country>
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<wicri:noRegion>2200 Copenhagen N</wicri:noRegion>
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<series><title level="j">Biochemistry</title>
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<term>Humans</term>
<term>Influenza A Virus, H2N2 Subtype (chemistry)</term>
<term>Influenza A Virus, H2N2 Subtype (genetics)</term>
<term>Influenza A Virus, H2N2 Subtype (metabolism)</term>
<term>Influenza A Virus, H3N2 Subtype (chemistry)</term>
<term>Influenza A Virus, H3N2 Subtype (genetics)</term>
<term>Influenza A Virus, H3N2 Subtype (metabolism)</term>
<term>Ion Channels (antagonists & inhibitors)</term>
<term>Ion Channels (chemistry)</term>
<term>Ion Channels (metabolism)</term>
<term>Ion Transport (drug effects)</term>
<term>Mutation, Missense</term>
<term>Protons</term>
<term>Structure-Activity Relationship</term>
<term>Viral Matrix Proteins (antagonists & inhibitors)</term>
<term>Viral Matrix Proteins (chemistry)</term>
<term>Viral Matrix Proteins (genetics)</term>
<term>Viral Matrix Proteins (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Canaux ioniques ()</term>
<term>Canaux ioniques (antagonistes et inhibiteurs)</term>
<term>Canaux ioniques (métabolisme)</term>
<term>Humains</term>
<term>Mutation faux-sens</term>
<term>Protons</term>
<term>Protéines de la matrice virale ()</term>
<term>Protéines de la matrice virale (antagonistes et inhibiteurs)</term>
<term>Protéines de la matrice virale (génétique)</term>
<term>Protéines de la matrice virale (métabolisme)</term>
<term>Relation structure-activité</term>
<term>Sous-type H2N2 du virus de la grippe A ()</term>
<term>Sous-type H2N2 du virus de la grippe A (génétique)</term>
<term>Sous-type H2N2 du virus de la grippe A (métabolisme)</term>
<term>Sous-type H3N2 du virus de la grippe A ()</term>
<term>Sous-type H3N2 du virus de la grippe A (génétique)</term>
<term>Sous-type H3N2 du virus de la grippe A (métabolisme)</term>
<term>Substitution d'acide aminé</term>
<term>Transport des ions ()</term>
</keywords>
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<term>Viral Matrix Proteins</term>
</keywords>
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<term>Protéines de la matrice virale</term>
</keywords>
<keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Influenza A Virus, H2N2 Subtype</term>
<term>Influenza A Virus, H3N2 Subtype</term>
<term>Ion Channels</term>
<term>Viral Matrix Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Ion Transport</term>
</keywords>
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<term>Influenza A Virus, H3N2 Subtype</term>
<term>Viral Matrix Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines de la matrice virale</term>
<term>Sous-type H2N2 du virus de la grippe A</term>
<term>Sous-type H3N2 du virus de la grippe A</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Influenza A Virus, H2N2 Subtype</term>
<term>Influenza A Virus, H3N2 Subtype</term>
<term>Ion Channels</term>
<term>Viral Matrix Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Canaux ioniques</term>
<term>Protéines de la matrice virale</term>
<term>Sous-type H2N2 du virus de la grippe A</term>
<term>Sous-type H3N2 du virus de la grippe A</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term>
<term>Humans</term>
<term>Mutation, Missense</term>
<term>Protons</term>
<term>Structure-Activity Relationship</term>
</keywords>
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<term>Humains</term>
<term>Mutation faux-sens</term>
<term>Protons</term>
<term>Protéines de la matrice virale</term>
<term>Relation structure-activité</term>
<term>Sous-type H2N2 du virus de la grippe A</term>
<term>Sous-type H3N2 du virus de la grippe A</term>
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<front><div type="abstract" xml:lang="en">The M2 protein is an important target for drugs in the fight against the influenza virus. Because of the emergence of resistance against antivirals directed toward the M2 proton channel, the search for new drugs against resistant M2 variants is of high importance. Robust and sensitive assays for testing potential drug compounds on different M2 variants are valuable tools in this search for new inhibitors. In this work, we describe a fluorescence sensor-based assay, which we termed "pHlux", that measures proton conduction through M2 when synthesized from an expression vector in Escherichia coli. The assay was compared to a previously established bacterial potassium ion transport complementation assay, and the results were compared to simulations obtained from analysis of a computational model of M2 and its interaction with inhibitor molecules. The inhibition of M2 was measured for five different inhibitors, including Rimantadine, Amantadine, and spiro type compounds, and the drug resistance of the M2 mutant variants (swine flu, V27A, and S31N) was confirmed. We demonstrate that the pHlux assay is robust and highly sensitive and shows potential for high-throughput screening.</div>
</front>
</TEI>
<affiliations><list><country><li>Danemark</li>
<li>Israël</li>
</country>
</list>
<tree><country name="Danemark"><noRegion><name sortKey="Santner, Paul" sort="Santner, Paul" uniqKey="Santner P" first="Paul" last="Santner">Paul Santner</name>
</noRegion>
<name sortKey="Behrendt, Lars" sort="Behrendt, Lars" uniqKey="Behrendt L" first="Lars" last="Behrendt">Lars Behrendt</name>
<name sortKey="Laursen, Jonas S" sort="Laursen, Jonas S" uniqKey="Laursen J" first="Jonas S" last="Laursen">Jonas S. Laursen</name>
<name sortKey="Lindorff Larsen, Kresten" sort="Lindorff Larsen, Kresten" uniqKey="Lindorff Larsen K" first="Kresten" last="Lindorff-Larsen">Kresten Lindorff-Larsen</name>
<name sortKey="Martins, Joao Miguel Da Silva" sort="Martins, Joao Miguel Da Silva" uniqKey="Martins J" first="João Miguel Da Silva" last="Martins">João Miguel Da Silva Martins</name>
<name sortKey="Olsen, Christian A" sort="Olsen, Christian A" uniqKey="Olsen C" first="Christian A" last="Olsen">Christian A. Olsen</name>
<name sortKey="Riber, Leise" sort="Riber, Leise" uniqKey="Riber L" first="Leise" last="Riber">Leise Riber</name>
<name sortKey="Willemoes, Martin" sort="Willemoes, Martin" uniqKey="Willemoes M" first="Martin" last="Willemoës">Martin Willemoës</name>
<name sortKey="Winther, Jakob R" sort="Winther, Jakob R" uniqKey="Winther J" first="Jakob R" last="Winther">Jakob R. Winther</name>
</country>
<country name="Israël"><noRegion><name sortKey="Arkin, Isaiah T" sort="Arkin, Isaiah T" uniqKey="Arkin I" first="Isaiah T" last="Arkin">Isaiah T. Arkin</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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