Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea

Pseurotin A2 and Azaspirofuran A

Daniëlle Copmans, Mostafa Rateb, Jioji N Tabudravu, Mercedes Pérez-Bonilla, Nina Dirkx, Riccardo Vallorani, Caridad Diaz, José Pérez Del Palacio, Alan J Smith, Rainer Ebel, Fernando Reyes, Marcel Jaspars, Peter A M de Witte

Research output: Contribution to journalArticle

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Abstract

In search for novel antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A2, pseurotin F1, 11- O-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus Aspergillus fumigatus, and their antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A2 and azaspirofuran A were identified as antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A2 and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were analyzed in the mouse 6 Hz (44 mA) psychomotor seizure model. They lowered the seizure duration dose-dependently, thereby confirming their antiseizure properties and suggesting activity against drug-resistant seizures. Finally, in a thorough ADMET assessment, pseurotin A2 and azaspirofuran A were found to be drug-like. Based on the prominent antiseizure activity in both species and the drug-likeness, we propose pseurotin A2 and azaspirofuran A as lead compounds that are worth further investigation for the treatment of epileptic seizures. This study not only provides the first evidence of antiseizure activity of pseurotins and azaspirofurans, but also demonstrates the value of the zebrafish model in (marine) natural product drug discovery in general, and for ASD discovery in particular.

Original languageEnglish
Pages (from-to)1652-1662
Number of pages11
JournalACS Chemical Neuroscience
Volume9
Issue number7
Early online date19 Apr 2018
DOIs
Publication statusPublished - 2018

Fingerprint

Indian Ocean
Zebrafish
varespladib methyl
Seizures
Drug Discovery
Pentylenetetrazole
Biological Products
Pharmaceutical Preparations
Lead compounds
pseurotin
azaspirofuran A
Lactams
Aspergillus fumigatus
Aspergillus
Mesencephalon
Fungi
Larva
Epilepsy
Embryonic Structures

Keywords

  • Journal Article
  • epilepsy
  • antiseizure drug discovery
  • marine drug discovery
  • pseurotin A
  • azaspirofuran A
  • aspergillus fumigatus

Cite this

Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea : Pseurotin A2 and Azaspirofuran A. / Copmans, Daniëlle; Rateb, Mostafa; Tabudravu, Jioji N; Pérez-Bonilla, Mercedes; Dirkx, Nina; Vallorani, Riccardo; Diaz, Caridad; Pérez Del Palacio, José; Smith, Alan J; Ebel, Rainer; Reyes, Fernando; Jaspars, Marcel; de Witte, Peter A M.

In: ACS Chemical Neuroscience, Vol. 9, No. 7, 2018, p. 1652-1662.

Research output: Contribution to journalArticle

Copmans, D, Rateb, M, Tabudravu, JN, Pérez-Bonilla, M, Dirkx, N, Vallorani, R, Diaz, C, Pérez Del Palacio, J, Smith, AJ, Ebel, R, Reyes, F, Jaspars, M & de Witte, PAM 2018, 'Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A', ACS Chemical Neuroscience, vol. 9, no. 7, pp. 1652-1662. https://doi.org/10.1021/acschemneuro.8b00060
Copmans, Daniëlle ; Rateb, Mostafa ; Tabudravu, Jioji N ; Pérez-Bonilla, Mercedes ; Dirkx, Nina ; Vallorani, Riccardo ; Diaz, Caridad ; Pérez Del Palacio, José ; Smith, Alan J ; Ebel, Rainer ; Reyes, Fernando ; Jaspars, Marcel ; de Witte, Peter A M. / Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea : Pseurotin A2 and Azaspirofuran A. In: ACS Chemical Neuroscience. 2018 ; Vol. 9, No. 7. pp. 1652-1662.
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AU - Copmans, Daniëlle

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AU - Tabudravu, Jioji N

AU - Pérez-Bonilla, Mercedes

AU - Dirkx, Nina

AU - Vallorani, Riccardo

AU - Diaz, Caridad

AU - Pérez Del Palacio, José

AU - Smith, Alan J

AU - Ebel, Rainer

AU - Reyes, Fernando

AU - Jaspars, Marcel

AU - de Witte, Peter A M

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AB - In search for novel antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A2, pseurotin F1, 11- O-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus Aspergillus fumigatus, and their antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A2 and azaspirofuran A were identified as antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A2 and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were analyzed in the mouse 6 Hz (44 mA) psychomotor seizure model. They lowered the seizure duration dose-dependently, thereby confirming their antiseizure properties and suggesting activity against drug-resistant seizures. Finally, in a thorough ADMET assessment, pseurotin A2 and azaspirofuran A were found to be drug-like. Based on the prominent antiseizure activity in both species and the drug-likeness, we propose pseurotin A2 and azaspirofuran A as lead compounds that are worth further investigation for the treatment of epileptic seizures. This study not only provides the first evidence of antiseizure activity of pseurotins and azaspirofurans, but also demonstrates the value of the zebrafish model in (marine) natural product drug discovery in general, and for ASD discovery in particular.

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KW - azaspirofuran A

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