title: Inhibition of Tapeworm Thioredoxin and Glutathione Pathways by an Oxadiazole N-Oxide Leads to Reduced Mesocestoides vogae Infection Burden in Mice.
abstract: Parasitic flatworms cause serious infectious diseases that affect humans and livestock in vast regions of the world, yet there are few effective drugs to treat them. Thioredoxin glutathione reductase (TGR) is an essential enzyme for redox homeostasis in flatworm parasites and a promising pharmacological target. We purified to homogeneity and characterized the TGR from the tapeworm Mesocestoides vogae (syn. M. corti). This purification revealed absence of conventional TR and GR. The glutathione reductase activity of the purified TGR exhibits a hysteretic behavior typical of flatworm TGRs. Consistently, M. vogae genome analysis revealed the presence of a selenocysteine-containing TGR and absence of conventional TR and GR. M. vogae thioredoxin and glutathione reductase activities were inhibited by 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole N2-oxide (VL16E), an oxadiazole N-oxide previously identified as an inhibitor of fluke and tapeworm TGRs. Finally, we show that mice experimentally infected with M. vogae tetrathyridia and treated with either praziquantel, the reference drug for flatworm infections, or VL16E exhibited a 28% reduction of intraperitoneal larvae numbers compared to vehicle treated mice. Our results show that oxadiazole N-oxide is a promising chemotype in vivo and highlights the convenience of M. vogae as a model for rapid assessment of tapeworm infections in vivo.
authors.affiliation: Inmunología, Instituto de Higiene, Facultad de Química, Universidad de la República, Avda, A. Navarro 3051, Montevideo 11400, Uruguay. vivianpasquet@web.de.
authors.forename: Vivian
authors.initials: V
authors.lastname: Pasquet
authors.affiliation: Worm Biology Laboratory, Institut Pasteur Montevideo, Mataojo 2020, Montevideo 11400, Uruguay. bisioh@pasteur.edu.uy.
authors.forename: Hugo
authors.initials: H
authors.lastname: Bisio
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay. vlopez@fq.edu.uy.
authors.forename: Gloria V
authors.initials: GV
authors.lastname: López
authors.affiliation: Worm Biology Laboratory, Institut Pasteur Montevideo, Mataojo 2020, Montevideo 11400, Uruguay. lromanelli@pasteur.edu.uy.
authors.forename: Laura
authors.initials: L
authors.lastname: Romanelli-Cedrez
authors.affiliation: Redox Biology of Trypanosomes Laboratory, Institut Pasteur Montevideo, Mataojo 2020, Montevideo 11400, Uruguay. mbonilla@pasteur.edu.uy.
authors.forename: Mariana
authors.initials: M
authors.lastname: Bonilla
authors.affiliation: Laboratorio de Experimentación Animal, Depto de Ciencias Farmacéuticas, Facultad de Química, Universidad de la República, Avda. Gral. Flores 2124, Montevideo 11800, Uruguay. jennysal@fq.edu.uy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Saldaña
authors.affiliation: Inmunología, Instituto de Higiene, Facultad de Química, Universidad de la República, Avda, A. Navarro 3051, Montevideo 11400, Uruguay. gsalin@fq.edu.uy.|Worm Biology Laboratory, Institut Pasteur Montevideo, Mataojo 2020, Montevideo 11400, Uruguay. gsalin@fq.edu.uy.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salinas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002589:Cestoda / Q000187:drug effects* / Q000378:metabolism; D002590:Cestode Infections / Q000469:parasitology*; D008645:Mesocestoides; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid
chemical_list: D009097:Multienzyme Complexes; D010069:Oxadiazoles; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase
keywords: Mesocestoides; glutathione reductase; oxadiazole N-oxide; tapeworms; thioredoxin glutathione reductase; thioredoxin reductase