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- Title
Phenotypic Evaluation of Nucleoside Analogues against Trypanosoma cruzi Infection: In Vitro and In Vivo Approaches.
- Authors
Fiuza, Ludmila F. de A.; Batista, Denise G. J.; Girão, Roberson D.; Hulpia, Fabian; Finamore-Araújo, Paula; Aldfer, Mustafa M.; Elmahallawy, Ehab Kotb; De Koning, Harry P.; Moreira, Otacílio; Van Calenbergh, Serge; Soeiro, Maria de Nazaré C.
- 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 3′-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 μM, 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.
- Subjects
TRYPANOSOMA cruzi; CHAGAS' disease; NUCLEOSIDE transport proteins; GENE amplification; LABORATORY mice
- Publication
Molecules, 2022, Vol 27, Issue 22, p8087
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules27228087