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COMBINATION WITH TOMATIDINE IMPROVES THE POTENCY OF POSACONAZOLE AGAINST TRYPANOSOMA CRUZI
Trypanosoma cruzi
Cloridrato de tomatidina
Inibidor da biossíntese de lipídios
Combinação de drogas
Tomatidine hydrochloride
Drug combination
Trypanosoma cruzi
Lipid biosynthesis inhibitor
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil / Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Systems Biology of Lipid Metabolism in Human Health and Diseases Laboratory, Lee Kong Chian School of Medicine. Singapore, Singapore.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Systems Biology of Lipid Metabolism in Human Health and Diseases Laboratory, Lee Kong Chian School of Medicine. Singapore, Singapore.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
Abstract
Azoles such as posaconazole (Posa) are highly potent against Trypanosoma cruzi.
However, when tested in chronic Chagas disease patients, a high rate of relapse after
Posa treatment was observed. It appears that inhibition of T. cruzi cytochrome CYP51, the
target of azoles, does not deliver sterile cure in monotherapy. Looking for suitable
combination partners of azoles, we have selected a set of inhibitors of sterol and
sphingolipid biosynthetic enzymes. A small-scale phenotypic screening was conducted
in vitro against the proliferative forms of T. cruzi, extracellular epimastigotes and
intracellular amastigotes. Against the intracellular, clinically relevant forms, four out of 15
tested compounds presented higher or equal activity as benznidazole (Bz), with EC50
values ≤2.2 mM. Ro48-8071, an inhibitor of lanosterol synthase (ERG7), and the steroidal
alkaloid tomatidine (TH), an inhibitor of C-24 sterol methyltransferase (ERG6), exhibited the
highest potency and selectivity indices (SI = 12 and 115, respectively). Both were directed
to combinatory assays using fixed-ratio protocols with Posa, Bz, and fexinidazole. The
combination of TH with Posa displayed a synergistic profile against amastigotes, with a
mean SFICI value of 0.2. In vivo assays using an acute mouse model of T. cruzi infection
demonstrated lack of antiparasitic activity of TH alone in doses ranging from 0.5 to 5 mg/
kg. As observed in vitro, the best combo proportion in vivo was the ratio 3 TH:1 Posa. The
combination of Posa at 1.25 mpk plus TH at 3.75 mpk displayed suppression of peak
parasitemia of 80% and a survival rate of 60% in the acute infection model, as compared
to 20% survival for Posa at 1.25 mpk alone and 40% for Posa at 10 mpk alone. These
initial results indicate a potential for the combination of posaconazole with tomatidine
against T. cruzi.
Keywords in Portuguese
Doença de ChagasTrypanosoma cruzi
Cloridrato de tomatidina
Inibidor da biossíntese de lipídios
Combinação de drogas
Keywords
Chagas DiseaseTomatidine hydrochloride
Drug combination
Trypanosoma cruzi
Lipid biosynthesis inhibitor
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