Anti-<i>Trypanosoma cruzi</i> Properties of Sesquiterpene Lactones Isolated from <i>Stevia</i> spp.: In Vitro and In Silico Studies
Jimena Borgo,
Orlando G. Elso,
Jessica Gomez,
Mauro Coll,
Cesar A. N. Catalán,
Juan Mucci,
Guzmán Alvarez,
Lía M. Randall,
Patricia Barrera,
Emilio L. Malchiodi,
Augusto E. Bivona,
María Florencia Martini,
Valeria P. Sülsen
Affiliations
Jimena Borgo
Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, piso 2, Buenos Aires C1113AAD, Argentina
Orlando G. Elso
Cátedra de Farmacognosia, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, piso 2, Buenos Aires C1113AAD, Argentina
Jessica Gomez
Facultad de Ciencias Médicas, Instituto de Histología y Embriología “Dr. Mario H. Burgos” (IHEM), Universidad Nacional de Cuyo-CONICET, CC 56, Mendoza 5500, Argentina
Mauro Coll
Facultad de Ciencias Médicas, Instituto de Histología y Embriología “Dr. Mario H. Burgos” (IHEM), Universidad Nacional de Cuyo-CONICET, CC 56, Mendoza 5500, Argentina
Cesar A. N. Catalán
Instituto de Química Orgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, San Miguel de Tucumán, Tucumán T4000INI, Argentina
Juan Mucci
Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín-CONICET, Buenos Aires 5500, Argentina
Guzmán Alvarez
Laboratorio de Moléculas Bioactivas, Departamento de Ciencias Biológicas, CENUR Litoral Norte, Universidad de la República, Paysandú 60000, Uruguay
Lía M. Randall
Laboratorio de Moléculas Bioactivas, Departamento de Ciencias Biológicas, CENUR Litoral Norte, Universidad de la República, Paysandú 60000, Uruguay
Patricia Barrera
Facultad de Ciencias Médicas, Instituto de Histología y Embriología “Dr. Mario H. Burgos” (IHEM), Universidad Nacional de Cuyo-CONICET, CC 56, Mendoza 5500, Argentina
Emilio L. Malchiodi
Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, piso 4, Buenos Aires C1113AAD, Argentina
Augusto E. Bivona
Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, piso 4, Buenos Aires C1113AAD, Argentina
María Florencia Martini
Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, piso 2, Buenos Aires C1113AAD, Argentina
Valeria P. Sülsen
Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), CONICET-Universidad de Buenos Aires, Junín 956, piso 2, Buenos Aires C1113AAD, Argentina
Stevia species (Asteraceae) have been a rich source of terpenoid compounds, mainly sesquiterpene lactones, several of which show antiprotozoal activity. In the search for new trypanocidal compounds, S. satureiifolia var. satureiifolia and S. alpina were studied. Two sesquiterpene lactones, santhemoidin C and 2-oxo-8-deoxyligustrin, respectively, were isolated. These compounds were assessed in vitro against Trypanosoma cruzi stages, showing IC50 values of 11.80 and 4.98 on epimastigotes, 56.08 and 26.19 on trypomastigotes and 4.88 and 20.20 µM on amastigotes, respectively. Cytotoxicity was evaluated on Vero cells by the MTT assay. The effect of the compounds on trypanothyone reductase (TcTR), Trans-sialidase (TcTS) and the prolyl oligopeptidase of 80 kDa (Tc80) as potential molecular targets of T. cruzi was investigated. Santhemoidin C inhibited oligopeptidase activity when tested against recombinant Tc80 using a fluorometric assay, reaching an IC50 of 34.9 µM. Molecular docking was performed to study the interaction between santhemoidin C and the Tc80 protein, reaching high docking energy levels. Plasma membrane shedding and cytoplasmic vacuoles, resembling autophagosomes, were detected by transmission microscopy in parasites treated with santhemoidin C. Based on these results, santhemoidin C represents a promising candidate for further studies in the search for new molecules for the development of trypanocidal drugs.
