INVESTIGADORES
BOUZAT Cecilia Beatriz
congresos y reuniones científicas
Título:
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity
Autor/es:
TURANI, O.; CASTRO, M.J.; FARAONI, M.B.; BOUZAT, C.B.
Reunión:
Jornada; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19; 2020
Institución organizadora:
Sociedad Argentina de Biofísica (SAB)
Resumen:
Nematode parasitosts causes mortality and morbidity in humans and losses in livestockand domestic animals. The acquisition of resistaoce to current anthetmintic drugs hasprompted the search for new compounds for which the nematode Caenothabditiselegans has emerged as a valuable platform. We have previously synthetized a library ofcompounds and determined that dibenzo(b,e}oxepin-11(6H)-one (doxepinone) reducesswimming rate, induces paralysis, and decreases the rate of pharyngeal pumpilg on C.elegans. To identify the drug targets, we perfomed a screening of strains canyingmutations in Cys-loop receptors invotved in worm locomotion for determining resistanceto doxepinone effects. A mutant strain that lacks subunit genes of the g1utamit.e-iJatedchloride channels (GluCI, which are targets of the antiparasitic ivermectin, is resistant todoxepioone effects. To unravel the molecular mechanism, we measured whote-cellcurrents from Glucl), receptors expressed in mammalian cells. Glutamate elicitsmacroscopic currents whereas no responses are elicited by doxepinone, indicating that itis not an agonist of GluCls. Preincubation of the cell with doxepinone produces asignificant decrease of the decay time constant and net charge of glutamate-elicitedcurrents. indicating that it inhibits GluCls. Thus, we identify doxepioone as an attractivescaffotd with promtsing anthelmintic activity and propose the iohibltion of GluCls as apotential anthelmintic mechanism of action.