| Autor: |
Fiuza LFA; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, 4365 Manguinhos, Rio de Janeiro 21040-360, Brazil., Batista DGJ; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, 4365 Manguinhos, Rio de Janeiro 21040-360, Brazil., Girão RD; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, 4365 Manguinhos, Rio de Janeiro 21040-360, Brazil., Hulpia F; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium., Finamore-Araújo P; Laboratório de Virologia Molecular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro 20000-000, Brazil., Aldfer MM; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow 62694, UK., Elmahallawy EK; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow 62694, UK.; Department of Zoonoses, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt., De Koning HP; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow 62694, UK., Moreira O; Laboratório de Virologia Molecular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro 20000-000, Brazil., Van Calenbergh S; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium., Soeiro MNC; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, 4365 Manguinhos, Rio de Janeiro 21040-360, Brazil. |
| Abstrakt: |
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. |
