Random Mutagenesis Analysis of the Influenza A M2 Proton Channel Reveals Novel Resistance Mutants.
Identifieur interne : 000164 ( Main/Exploration ); précédent : 000163; suivant : 000165Random Mutagenesis Analysis of the Influenza A M2 Proton Channel Reveals Novel Resistance Mutants.
Auteurs : Paul Santner [Danemark] ; João Miguel Da Silva Martins [Danemark] ; Caroline Kampmeyer [Danemark] ; Rasmus Hartmann-Petersen [Danemark] ; Jonas S. Laursen [Danemark] ; Amelie Stein [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 :
- Antiviraux (), Antiviraux (pharmacologie), Canaux ioniques (), Canaux ioniques (antagonistes et inhibiteurs), Canaux ioniques (génétique), Canaux ioniques (métabolisme), Escherichia coli, Humains, Mutagenèse, Mutation faux-sens, 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), Résistance virale aux médicaments (génétique), 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.
- MESH :
- antagonistes et inhibiteurs : Canaux ioniques, Protéines de la matrice virale.
- génétique : Canaux ioniques, Protéines de la matrice virale, Résistance virale aux médicaments, 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.
- pharmacologie : Antiviraux.
- Antiviraux, Canaux ioniques, Escherichia coli, Humains, Mutagenèse, Mutation faux-sens, Protéines de la matrice virale, Sous-type H2N2 du virus de la grippe A, Sous-type H3N2 du virus de la grippe A, Substitution d'acide aminé.
English descriptors
- KwdEn :
- Amino Acid Substitution, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Drug Resistance, Viral (genetics), Escherichia coli, 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 (genetics), Ion Channels (metabolism), Mutagenesis, Mutation, Missense, 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.
- chemical , chemistry : Antiviral Agents, Ion Channels, Viral Matrix Proteins.
- chemical , genetics : Ion Channels, Viral Matrix Proteins.
- chemical , metabolism : Ion Channels, Viral Matrix Proteins.
- chemical , pharmacology : Antiviral Agents.
- chemistry : Influenza A Virus, H2N2 Subtype, Influenza A Virus, H3N2 Subtype.
- genetics : Drug Resistance, Viral, Influenza A Virus, H2N2 Subtype, Influenza A Virus, H3N2 Subtype.
- metabolism : Influenza A Virus, H2N2 Subtype, Influenza A Virus, H3N2 Subtype.
- Amino Acid Substitution, Escherichia coli, Humans, Mutagenesis, Mutation, Missense.
Abstract
The influenza M2 proton channel is a major drug target, but unfortunately, the acquisition of resistance mutations greatly reduces the functional life span of a drug in influenza treatment. New M2 inhibitors that inhibit mutant M2 channels otherwise resistant to the early adamantine-based drugs have been reported, but it remains unclear whether and how easy resistance could arise to such inhibitors. We have combined a newly developed proton conduction assay with an established method for selection and screening, both Escherichia coli-based, to enable the study of M2 function and inhibition. Combining this platform with two groups of structurally different M2 inhibitors allowed us to isolate drug resistant M2 channels from a mutant library. Two groups of M2 variants emerged from this analysis. A first group appeared almost unaffected by the inhibitor, M_089 (N13I, I35L, and F47L) and M_272 (G16C and D44H), and the single-substitution variants derived from these (I35L, L43P, D44H, and L46P). Functionally, these resemble the known drug resistant M2 channels V27A, S31N, and swine flu. In addition, a second group of tested M2 variants were all still inhibited by drugs but to a lesser extent than wild type M2. Molecular dynamics simulations aided in distinguishing the two groups where drug binding to the wild type and the less resistant M2 group showed a stable positioning of the ligand in the canonical binding pose, as opposed to the drug resistant group in which the ligand rapidly dissociated from the complex during the simulations.
DOI: 10.1021/acs.biochem.8b00722
PubMed: 30230310
Affiliations:
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Le document en format XML
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Silva" uniqKey="Martins J" first="João Miguel Da Silva" last="Martins">João Miguel Da Silva Martins</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><wicri:noRegion>2200 Copenhagen N</wicri:noRegion></affiliation></author><author><name sortKey="Kampmeyer, Caroline" sort="Kampmeyer, Caroline" uniqKey="Kampmeyer C" first="Caroline" last="Kampmeyer">Caroline Kampmeyer</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><wicri:noRegion>2200 Copenhagen N</wicri:noRegion></affiliation></author><author><name sortKey="Hartmann Petersen, Rasmus" sort="Hartmann Petersen, Rasmus" uniqKey="Hartmann Petersen R" first="Rasmus" last="Hartmann-Petersen">Rasmus Hartmann-Petersen</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><wicri:noRegion>2200 Copenhagen N</wicri:noRegion></affiliation></author><author><name sortKey="Laursen, Jonas S" sort="Laursen, Jonas S" uniqKey="Laursen J" first="Jonas S" last="Laursen">Jonas S. Laursen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , 2100 Copenhagen , Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , 2100 Copenhagen </wicri:regionArea><wicri:noRegion>2100 Copenhagen </wicri:noRegion></affiliation></author><author><name sortKey="Stein, Amelie" sort="Stein, Amelie" uniqKey="Stein A" first="Amelie" last="Stein">Amelie Stein</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><wicri:noRegion>2200 Copenhagen N</wicri:noRegion></affiliation></author><author><name sortKey="Olsen, Christian A" sort="Olsen, Christian A" uniqKey="Olsen C" first="Christian A" last="Olsen">Christian A. Olsen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , 2100 Copenhagen , Denmark.</nlm:affiliation><country xml:lang="fr">Danemark</country><wicri:regionArea>Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , 2100 Copenhagen </wicri:regionArea><wicri:noRegion>2100 Copenhagen </wicri:noRegion></affiliation></author><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><wicri:noRegion>Jerusalem 91904 </wicri:noRegion></affiliation></author><author><name sortKey="Winther, Jakob R" sort="Winther, Jakob R" uniqKey="Winther J" first="Jakob R" last="Winther">Jakob R. Winther</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><wicri:noRegion>2200 Copenhagen N</wicri:noRegion></affiliation></author><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><wicri:noRegion>2200 Copenhagen N</wicri:noRegion></affiliation></author><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><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></affiliation></author></analytic><series><title level="j">Biochemistry</title><idno type="eISSN">1520-4995</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Substitution</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Drug Resistance, Viral (genetics)</term><term>Escherichia coli</term><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 (genetics)</term><term>Ion Channels (metabolism)</term><term>Mutagenesis</term><term>Mutation, Missense</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>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Canaux ioniques ()</term><term>Canaux ioniques (antagonistes et inhibiteurs)</term><term>Canaux ioniques (génétique)</term><term>Canaux ioniques (métabolisme)</term><term>Escherichia coli</term><term>Humains</term><term>Mutagenèse</term><term>Mutation faux-sens</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>Résistance virale aux médicaments (génétique)</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></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Ion Channels</term><term>Viral Matrix Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Ion Channels</term><term>Viral Matrix Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Ion Channels</term><term>Viral Matrix Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Ion Channels</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="antagonistes et inhibiteurs" xml:lang="fr"><term>Canaux ioniques</term><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></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Drug Resistance, Viral</term><term>Influenza A Virus, H2N2 Subtype</term><term>Influenza A Virus, H3N2 Subtype</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Canaux ioniques</term><term>Protéines de la matrice virale</term><term>Résistance virale aux médicaments</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></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" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term><term>Escherichia coli</term><term>Humans</term><term>Mutagenesis</term><term>Mutation, Missense</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term><term>Canaux ioniques</term><term>Escherichia coli</term><term>Humains</term><term>Mutagenèse</term><term>Mutation faux-sens</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><term>Substitution d'acide aminé</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The influenza M2 proton channel is a major drug target, but unfortunately, the acquisition of resistance mutations greatly reduces the functional life span of a drug in influenza treatment. New M2 inhibitors that inhibit mutant M2 channels otherwise resistant to the early adamantine-based drugs have been reported, but it remains unclear whether and how easy resistance could arise to such inhibitors. We have combined a newly developed proton conduction assay with an established method for selection and screening, both Escherichia coli-based, to enable the study of M2 function and inhibition. Combining this platform with two groups of structurally different M2 inhibitors allowed us to isolate drug resistant M2 channels from a mutant library. Two groups of M2 variants emerged from this analysis. A first group appeared almost unaffected by the inhibitor, M_089 (N13I, I35L, and F47L) and M_272 (G16C and D44H), and the single-substitution variants derived from these (I35L, L43P, D44H, and L46P). Functionally, these resemble the known drug resistant M2 channels V27A, S31N, and swine flu. In addition, a second group of tested M2 variants were all still inhibited by drugs but to a lesser extent than wild type M2. Molecular dynamics simulations aided in distinguishing the two groups where drug binding to the wild type and the less resistant M2 group showed a stable positioning of the ligand in the canonical binding pose, as opposed to the drug resistant group in which the ligand rapidly dissociated from the complex during the simulations.</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="Hartmann Petersen, Rasmus" sort="Hartmann Petersen, Rasmus" uniqKey="Hartmann Petersen R" first="Rasmus" last="Hartmann-Petersen">Rasmus Hartmann-Petersen</name><name sortKey="Kampmeyer, Caroline" sort="Kampmeyer, Caroline" uniqKey="Kampmeyer C" first="Caroline" last="Kampmeyer">Caroline Kampmeyer</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="Stein, Amelie" sort="Stein, Amelie" uniqKey="Stein A" first="Amelie" last="Stein">Amelie Stein</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>Pour manipuler ce document sous Unix (Dilib)
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