From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin
PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and i...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/2/247 |
| _version_ | 1797477235963199488 |
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| author | Daniëlle Copmans Sara Kildgaard Emma Roux Michèle Partoens Gert Steurs Xinhui Wang Wim M. De Borggraeve Camila V. Esguerra Alexander D. Crawford Thomas O. Larsen Peter A. M. de Witte |
| author_facet | Daniëlle Copmans Sara Kildgaard Emma Roux Michèle Partoens Gert Steurs Xinhui Wang Wim M. De Borggraeve Camila V. Esguerra Alexander D. Crawford Thomas O. Larsen Peter A. M. de Witte |
| author_sort | Daniëlle Copmans |
| collection | DOAJ |
| description | PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin’s antiseizure action. |
| first_indexed | 2024-03-09T21:14:47Z |
| format | Article |
| id | doaj.art-367a45b4e88e4608b3466080bf98c684 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T21:14:47Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-367a45b4e88e4608b3466080bf98c6842023-11-23T21:35:23ZengMDPI AGPharmaceuticals1424-82472022-02-0115224710.3390/ph15020247From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and PlinabulinDaniëlle Copmans0Sara Kildgaard1Emma Roux2Michèle Partoens3Gert Steurs4Xinhui Wang5Wim M. De Borggraeve6Camila V. Esguerra7Alexander D. Crawford8Thomas O. Larsen9Peter A. M. de Witte10Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumDepartment of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, 2800 Kgs. Lyngby, DenmarkLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumMolecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200f box 2404, 3001 Leuven, BelgiumDepartment of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, 2800 Kgs. Lyngby, DenmarkMolecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200f box 2404, 3001 Leuven, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumDepartment of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, 2800 Kgs. Lyngby, DenmarkLaboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 box 824, 3000 Leuven, BelgiumPharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin’s antiseizure action.https://www.mdpi.com/1424-8247/15/2/247marine natural productsdrug discoveryepilepsyzebrafishplinabulinhalimide |
| spellingShingle | Daniëlle Copmans Sara Kildgaard Emma Roux Michèle Partoens Gert Steurs Xinhui Wang Wim M. De Borggraeve Camila V. Esguerra Alexander D. Crawford Thomas O. Larsen Peter A. M. de Witte From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin Pharmaceuticals marine natural products drug discovery epilepsy zebrafish plinabulin halimide |
| title | From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin |
| title_full | From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin |
| title_fullStr | From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin |
| title_full_unstemmed | From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin |
| title_short | From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin |
| title_sort | from the north sea to drug repurposing the antiseizure activity of halimide and plinabulin |
| topic | marine natural products drug discovery epilepsy zebrafish plinabulin halimide |
| url | https://www.mdpi.com/1424-8247/15/2/247 |
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