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Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases.
Coquerel, Quentin; Legendre, Claire; Frangieh, Jacinthe; Waard, Stephan De; Montnach, Jérôme; Cmarko, Leos; Khoury, Joseph; Hassane, Charifat Said; Bréard, Dimitri; Siegler, Benjamin; Fajloun, Ziad; De Pomyers, Harold; Mabrouk, Kamel; Weiss, Norbert; Henrion, Daniel; Richomme, Pascal; Mattei, César; Waard, Michel De; Le Ray, Anne-Marie; Legros, Christian.
Afiliación
  • Coquerel Q; Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France.
  • Legendre C; Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France.
  • Frangieh J; Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France.
  • Waard S; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du Thorax, 44000 Nantes, France.
  • Montnach J; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du Thorax, 44000 Nantes, France.
  • Cmarko L; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du Thorax, 44000 Nantes, France.
  • Khoury J; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du Thorax, 44000 Nantes, France.
  • Hassane CS; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic.
  • Bréard D; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10 Prague, Czech Republic.
  • Siegler B; Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France.
  • Fajloun Z; Laboratory of Applied Biotechnology, AZM Centre for Research in Biotechnology and Its Application, Doctoral School for Sciences and Technology, Tripoli 1352, Lebanon.
  • De Pomyers H; Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France.
  • Mabrouk K; Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France.
  • Weiss N; Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France.
  • Henrion D; Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France.
  • Richomme P; Laboratory of Applied Biotechnology, AZM Centre for Research in Biotechnology and Its Application, Doctoral School for Sciences and Technology, Tripoli 1352, Lebanon.
  • Mattei C; Latoxan Laboratory, 26800 Portes lès Valence, France.
  • Waard M; CNRS, ICR, Aix Marseille Univ, 13397 Marseille, France.
  • Le Ray AM; Department of Pathophysiology, First Faculty of Medicine, Charles University, 160 00 Prague, Czech Republic.
  • Legros C; Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France.
Molecules ; 27(13)2022 Jun 28.
Article en En | MEDLINE | ID: mdl-35807390
Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alcaloides / Colorantes Fluorescentes Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Humans Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alcaloides / Colorantes Fluorescentes Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Humans Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza