APA
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Coquerel, Q., Legendre, C., Frangieh, J., Waard, S. D., Montnach, J., Cmarko, L., … Legros, C. (2022). Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases. Molecules.
Chicago/Turabian
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Coquerel, Q., Claire Legendre, J. Frangieh, S. D. Waard, J. Montnach, Leos Cmarko, J. Khoury, et al. “Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases.” Molecules (2022).
MLA
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Coquerel, Q., et al. “Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases.” Molecules, 2022.
BibTeX Click to copy
@article{q2022a,
title = {Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases},
year = {2022},
journal = {Molecules},
author = {Coquerel, Q. and Legendre, Claire and Frangieh, J. and Waard, S. D. and Montnach, J. and Cmarko, Leos and Khoury, J. and Hassane, Charifat Said and Bréard, D. and Siegler, B. and Fajloun, Z. and de Pomyers, H. and Mabrouk, K. and Weiss, N. and Henrion, D. and Richomme, P. and Mattei, C. and Waard, M. and Ray, A. Le and Legros, C.}
}
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.
