Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication
Dengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C<sub>15</sub>H<sub>31</sub>C(O)-Lys-(Gly or Ala)<...
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MDPI AG
2022-05-01
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| Online Access: | https://www.mdpi.com/1420-3049/27/10/3217 |
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| author | Mark Damen Mario A. Izidoro Debora N. Okamoto Lilian C. G. Oliveira Helene I. V. Amatdjais-Groenen Stijn F. M. van Dongen Koen W. R. van Cleef Ronald P. van Rij Cindy E. J. Dieteren Daniel Gironés Bernd N. M. van Buuren Byron E. E. Martina Albert D. M. E. Osterhaus Luiz Juliano Bob J. Scholte Martin C. Feiters |
| author_facet | Mark Damen Mario A. Izidoro Debora N. Okamoto Lilian C. G. Oliveira Helene I. V. Amatdjais-Groenen Stijn F. M. van Dongen Koen W. R. van Cleef Ronald P. van Rij Cindy E. J. Dieteren Daniel Gironés Bernd N. M. van Buuren Byron E. E. Martina Albert D. M. E. Osterhaus Luiz Juliano Bob J. Scholte Martin C. Feiters |
| author_sort | Mark Damen |
| collection | DOAJ |
| description | Dengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C<sub>15</sub>H<sub>31</sub>C(O)-Lys-(Gly or Ala)<sub>n</sub>Lys-NHC<sub>16</sub>H<sub>33</sub>, shorthand notation C<sub>16</sub>-KX<sub>n</sub>K-C<sub>16</sub> with X = A or G, and <i>n</i> = 0–2). The representatives with 1 or 2 Ala inhibit dengue protease and human furin, two serine proteases involved in dengue virus infection that have peptides with cationic amino acids as their preferred substrates, with IC<sub>50</sub> values in the lower µM range. The geminoid C<sub>16</sub>-KAK-C<sub>16</sub> combined inhibition of DENV2 protease (IC<sub>50</sub> 2.3 µM) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC<sub>50</sub> 4.1 µM) and an absence of toxicity. We conclude that the lysine-based geminoids have activity against dengue virus infection, which is based on their inhibition of the proteases involved in viral replication and are therefore promising leads to further developing antiviral therapeutics, not limited to dengue. |
| first_indexed | 2024-03-10T03:20:33Z |
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| id | doaj.art-d084e2f6349a407ca6f90b3ddaeb881b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:20:33Z |
| publishDate | 2022-05-01 |
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| series | Molecules |
| spelling | doaj.art-d084e2f6349a407ca6f90b3ddaeb881b2023-11-23T12:22:54ZengMDPI AGMolecules1420-30492022-05-012710321710.3390/molecules27103217Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral ReplicationMark Damen0Mario A. Izidoro1Debora N. Okamoto2Lilian C. G. Oliveira3Helene I. V. Amatdjais-Groenen4Stijn F. M. van Dongen5Koen W. R. van Cleef6Ronald P. van Rij7Cindy E. J. Dieteren8Daniel Gironés9Bernd N. M. van Buuren10Byron E. E. Martina11Albert D. M. E. Osterhaus12Luiz Juliano13Bob J. Scholte14Martin C. Feiters15Department of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsDepartment of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, BrazilDepartment of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, BrazilDepartment of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, BrazilDepartment of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsDepartment of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsDepartment of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, The NetherlandsDepartment of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6500 HB Nijmegen, The NetherlandsProtinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The NetherlandsProtinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The NetherlandsProtinhi Therapeutics, Transistorweg 5, 6534 AT Nijmegen, The NetherlandsDepartment of Viroscience, Erasmus Medical Centre, 3015 GD Rotterdam, The NetherlandsArtemis Bio-Support, Molengraaffsingel 10, 2629 JD Delft, The NetherlandsDepartment of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio, 100, São Paulo 04044-020, BrazilDepartment of Cell Biology, Erasmus Medical Centre, 3000 CA Rotterdam, The NetherlandsDepartment of Organic Chemistry, Institute for Molecules and Materials, Faculty of Science, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsDengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C<sub>15</sub>H<sub>31</sub>C(O)-Lys-(Gly or Ala)<sub>n</sub>Lys-NHC<sub>16</sub>H<sub>33</sub>, shorthand notation C<sub>16</sub>-KX<sub>n</sub>K-C<sub>16</sub> with X = A or G, and <i>n</i> = 0–2). The representatives with 1 or 2 Ala inhibit dengue protease and human furin, two serine proteases involved in dengue virus infection that have peptides with cationic amino acids as their preferred substrates, with IC<sub>50</sub> values in the lower µM range. The geminoid C<sub>16</sub>-KAK-C<sub>16</sub> combined inhibition of DENV2 protease (IC<sub>50</sub> 2.3 µM) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC<sub>50</sub> 4.1 µM) and an absence of toxicity. We conclude that the lysine-based geminoids have activity against dengue virus infection, which is based on their inhibition of the proteases involved in viral replication and are therefore promising leads to further developing antiviral therapeutics, not limited to dengue.https://www.mdpi.com/1420-3049/27/10/3217amphiphilesdrug discoveryinhibitorsmembrane proteinspeptides |
| spellingShingle | Mark Damen Mario A. Izidoro Debora N. Okamoto Lilian C. G. Oliveira Helene I. V. Amatdjais-Groenen Stijn F. M. van Dongen Koen W. R. van Cleef Ronald P. van Rij Cindy E. J. Dieteren Daniel Gironés Bernd N. M. van Buuren Byron E. E. Martina Albert D. M. E. Osterhaus Luiz Juliano Bob J. Scholte Martin C. Feiters Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication Molecules amphiphiles drug discovery inhibitors membrane proteins peptides |
| title | Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication |
| title_full | Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication |
| title_fullStr | Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication |
| title_full_unstemmed | Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication |
| title_short | Cationic Geminoid Peptide Amphiphiles Inhibit DENV2 Protease, Furin, and Viral Replication |
| title_sort | cationic geminoid peptide amphiphiles inhibit denv2 protease furin and viral replication |
| topic | amphiphiles drug discovery inhibitors membrane proteins peptides |
| url | https://www.mdpi.com/1420-3049/27/10/3217 |
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