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PHENOTYPIC EVALUATION OF NUCLEOSIDE ANALOGUES AGAINST TRYPANOSOMA CRUZI INFECTION: IN VITRO AND IN VIVO APPROACHES
Trypanosoma cruzi
Quimioterapia experimental
Derivados de nucleosídeos
Transportador de timidina
Trypanosoma cruzi
Experimental chemotherapy
Nucleoside derivatives
Thymidine transporter
Author
Affilliation
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.
Ghent University. Laboratory for Medicinal Chemistry (Campus Heymans). 460, B-9000 Ghent, Belgium.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.
University of Glasgow. School of Infection and Immunity, College of Medical, Veterinary and Life Sciences. Glasgow, UK.
University of Glasgow. School of Infection and Immunity, College of Medical, Veterinary and Life Sciences. Glasgow, UK / Sohag University, Department of Zoonoses, Faculty of Veterinary Medicine. Sohag, Egypt.
University of Glasgow. School of Infection and Immunity, College of Medical, Veterinary and Life Sciences. Glasgow, UK.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.
Ghent University. Laboratory for Medicinal Chemistry (Campus Heymans). 460, B-9000 Ghent, Belgium.
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.
Ghent University. Laboratory for Medicinal Chemistry (Campus Heymans). 460, B-9000 Ghent, Belgium.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.
University of Glasgow. School of Infection and Immunity, College of Medical, Veterinary and Life Sciences. Glasgow, UK.
University of Glasgow. School of Infection and Immunity, College of Medical, Veterinary and Life Sciences. Glasgow, UK / Sohag University, Department of Zoonoses, Faculty of Veterinary Medicine. Sohag, Egypt.
University of Glasgow. School of Infection and Immunity, College of Medical, Veterinary and Life Sciences. Glasgow, UK.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.
Ghent University. Laboratory for Medicinal Chemistry (Campus Heymans). 460, B-9000 Ghent, Belgium.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Abstract
Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem.
Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy
and safety drawbacks. Nucleoside analogues represent a promising alternative as protozoans do not
biosynthesize purines and rely on purine salvage from the hosts. Protozoan transporters often present
different substrate specificities from mammalian transporters, justifying the exploration of nucleoside
analogues as therapeutic agents. Previous reports identified nucleosides with potent trypanocidal
activity; therefore, two 7-derivatized tubercidins (FH11706, FH10714) and a 30-deoxytubercidin
(FH8513) were assayed against T. cruzi. They were highly potent and selective, and the uptake of the
tubercidin analogues appeared to be mediated by the nucleoside transporter TcrNT2. At 10 M, the
analogues reduced parasitemia >90% in 2D and 3D cardiac cultures. The washout assays showed
that FH10714 sterilized the infected cultures. Given orally, the compounds did not induce noticeable
mouse toxicity (50 mg/kg), suppressed the parasitemia of T. cruzi-infected Swiss mice (25 mg/kg,
5 days) and presented DNA amplification below the limit of detection. These findings justify further
studies with longer treatment regimens, as well as evaluations in combination with nitro drugs,
aiming to identify more effective and safer therapies for Chagas disease.
Keywords in Portuguese
Doença de ChagasTrypanosoma cruzi
Quimioterapia experimental
Derivados de nucleosídeos
Transportador de timidina
Keywords
Chagas diseaseTrypanosoma cruzi
Experimental chemotherapy
Nucleoside derivatives
Thymidine transporter
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