Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses
Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine drugs inhibit influenza A M2 wild-type (WT; bearing in the protein M2 proton channel serine at position-31) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | European Journal of Medicinal Chemistry Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417422000553 |
| _version_ | 1811178179292823552 |
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| author | Christina Tzitzoglaki Anja Hoffmann Andreea L. Turcu Patrick Schmerer Chunlong Ma George Laros Christos Liolios Brea José Jun Wang Santiago Vázquez Michaela Schmidtke Antonios Kolocouris |
| author_facet | Christina Tzitzoglaki Anja Hoffmann Andreea L. Turcu Patrick Schmerer Chunlong Ma George Laros Christos Liolios Brea José Jun Wang Santiago Vázquez Michaela Schmidtke Antonios Kolocouris |
| author_sort | Christina Tzitzoglaki |
| collection | DOAJ |
| description | Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine drugs inhibit influenza A M2 wild-type (WT; bearing in the protein M2 proton channel serine at position-31) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant to these drugs influenza A viruses bearing the S31N mutant in the M2 proton channel can be inhibited by amantadine – aryl conjugates, in which amantadine and an aryl group are linked through a methylene, which block M2 S31N channel-mediated proton current. However, the M2 amantadine/rimantadine resistant viruses bearing one of the four mutations L26F, V27A, A30T, G34E in residues that line the M2 channel pore pose an additional concern for public health.Here, we designed 33 compounds based on the structure of three previously published and potent amantadine-aryl conjugates against M2 S31N virus, by replacing amantadine with 16 amantadine variants. The compounds were tested against M2 WT and the five M2 amantadine resistant viruses aiming at identifying inhibitors against multiple M2 mutant – amantadine resistant viruses.We identified 16 compounds that inhibited in vitro two influenza A viruses with M2 WT or L26F channels. Additionally, compounds 21 or 32 or 33, which are conjugates of the rimantadine variant with CMe2 (instead of CHMe in rimantadine) or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl aryl group, were in vitro inhibitors against three influenza A viruses with M2 WT or L26F or S31N, while compound 21 inhibited also in vitro the M2 G34E virus and compound 32 inhibited also in vitro the M2 A30T virus. Also, using electrophysiology, we showed that compound 21 was an efficient blocker of the M2 WT and M2 L26F channels, compound 32 blocked efficiently the M2 WT channel and compound 33 blocked the M2 WT, L26F and V27A channels. The drug metabolism and pharmacokinetics studies showed that these compounds need further optimization. |
| first_indexed | 2024-04-11T06:14:03Z |
| format | Article |
| id | doaj.art-61d646d119f84656a795a2586c903bd3 |
| institution | Directory Open Access Journal |
| issn | 2772-4174 |
| language | English |
| last_indexed | 2024-04-11T06:14:03Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj.art-61d646d119f84656a795a2586c903bd32022-12-22T04:41:06ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742022-12-016100083Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a virusesChristina Tzitzoglaki0Anja Hoffmann1Andreea L. Turcu2Patrick Schmerer3Chunlong Ma4George Laros5Christos Liolios6Brea José7Jun Wang8Santiago Vázquez9Michaela Schmidtke10Antonios Kolocouris11Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, GreeceJena University Hospital, Department of Medical Microbiology, Section Experimental Virology, CMB Building, R. 443, Hans Knoell Str. 2, D-07745, Jena, GermanyLaboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l’Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, SpainJena University Hospital, Department of Medical Microbiology, Section Experimental Virology, CMB Building, R. 443, Hans Knoell Str. 2, D-07745, Jena, GermanyDepartment of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United StatesLaboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, GreeceLaboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, GreeceDrug Screening Platform/Biofarma Research Group, CIMUS Research Center, Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, University of Santiago de Compostela (USC), 15782, Santiago de Compostela, SpainDepartment of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United StatesLaboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l’Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona, E-08028, SpainJena University Hospital, Department of Medical Microbiology, Section Experimental Virology, CMB Building, R. 443, Hans Knoell Str. 2, D-07745, Jena, Germany; Corresponding author.Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, Greece; Corresponding author.Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine drugs inhibit influenza A M2 wild-type (WT; bearing in the protein M2 proton channel serine at position-31) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant to these drugs influenza A viruses bearing the S31N mutant in the M2 proton channel can be inhibited by amantadine – aryl conjugates, in which amantadine and an aryl group are linked through a methylene, which block M2 S31N channel-mediated proton current. However, the M2 amantadine/rimantadine resistant viruses bearing one of the four mutations L26F, V27A, A30T, G34E in residues that line the M2 channel pore pose an additional concern for public health.Here, we designed 33 compounds based on the structure of three previously published and potent amantadine-aryl conjugates against M2 S31N virus, by replacing amantadine with 16 amantadine variants. The compounds were tested against M2 WT and the five M2 amantadine resistant viruses aiming at identifying inhibitors against multiple M2 mutant – amantadine resistant viruses.We identified 16 compounds that inhibited in vitro two influenza A viruses with M2 WT or L26F channels. Additionally, compounds 21 or 32 or 33, which are conjugates of the rimantadine variant with CMe2 (instead of CHMe in rimantadine) or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl aryl group, were in vitro inhibitors against three influenza A viruses with M2 WT or L26F or S31N, while compound 21 inhibited also in vitro the M2 G34E virus and compound 32 inhibited also in vitro the M2 A30T virus. Also, using electrophysiology, we showed that compound 21 was an efficient blocker of the M2 WT and M2 L26F channels, compound 32 blocked efficiently the M2 WT channel and compound 33 blocked the M2 WT, L26F and V27A channels. The drug metabolism and pharmacokinetics studies showed that these compounds need further optimization.http://www.sciencedirect.com/science/article/pii/S2772417422000553Amantadine - aryl conjugateIn vitro antiviral activityCPEElectrophysiologyInfluenza A M2 proteinA30T |
| spellingShingle | Christina Tzitzoglaki Anja Hoffmann Andreea L. Turcu Patrick Schmerer Chunlong Ma George Laros Christos Liolios Brea José Jun Wang Santiago Vázquez Michaela Schmidtke Antonios Kolocouris Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses European Journal of Medicinal Chemistry Reports Amantadine - aryl conjugate In vitro antiviral activity CPE Electrophysiology Influenza A M2 protein A30T |
| title | Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses |
| title_full | Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses |
| title_fullStr | Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses |
| title_full_unstemmed | Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses |
| title_short | Amantadine variant – aryl conjugates that inhibit multiple M2 mutant – amantadine resistant influenza a viruses |
| title_sort | amantadine variant aryl conjugates that inhibit multiple m2 mutant amantadine resistant influenza a viruses |
| topic | Amantadine - aryl conjugate In vitro antiviral activity CPE Electrophysiology Influenza A M2 protein A30T |
| url | http://www.sciencedirect.com/science/article/pii/S2772417422000553 |
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