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7-Aryl-7-deazapurine 3 '-deoxyribonucleoside derivative as a novel lead for Chagas' disease therapy : in vitro and in vivo pharmacology

Cardoso-Santos, Camila ; de Almeida Fiuza, Ludmila Ferreira ; da Silva, Cristiane Franca ; Mazzeti, Ana Lia ; Girao, Roberson Donola ; de Oliveira, Gabriel Melo ; Jaen Batista, Denise da Gama ; Moreira, Otacilio Cruz ; da Silva Gomes, Natalia Lins ; Maes, Louis ; Caljon, Guy ; Hulpia, Fabian ; Van Calenbergh, Serge ; Correia Soeiro, Maria de Nazare

2021

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  • Título:
    7-Aryl-7-deazapurine 3 '-deoxyribonucleoside derivative as a novel lead for Chagas' disease therapy : in vitro and in vivo pharmacology
  • Autor: Cardoso-Santos, Camila ; de Almeida Fiuza, Ludmila Ferreira ; da Silva, Cristiane Franca ; Mazzeti, Ana Lia ; Girao, Roberson Donola ; de Oliveira, Gabriel Melo ; Jaen Batista, Denise da Gama ; Moreira, Otacilio Cruz ; da Silva Gomes, Natalia Lins ; Maes, Louis ; Caljon, Guy ; Hulpia, Fabian ; Van Calenbergh, Serge ; Correia Soeiro, Maria de Nazare
  • Assuntos: ANALOGS ; CANCER ; Chemistry ; EFFICACY ; INFECTION ; Medicine and Health Sciences ; NUCLEOSIDE ; TRYPANOSOMA-CRUZI
  • Notas: ISSN: 2632-1823
    JAC-ANTIMICROBIAL RESISTANCE
  • Descrição: Background The protozoan Trypanosoma cruzi is auxotrophic for purines and causes Chagas' disease (CD), a neglected illness affecting >6 million people. Combining the 3-deoxyribofuranose part of cordycepin with the modified purine ring of a nucleoside 'hit' led to the discovery of 4-amino-5-(4-chlorophenyl)-N7-(3 '-deoxy-beta-d-ribofuranosyl)-pyrrolo[2,3-d]pyrimidine (Cpd1), revealing promising anti-T. cruzi activity. Objectives To further evaluate Cpd1 in vitro and in vivo to fully assess its therapeutic potential against CD, covering cell culture sterilization through washout assays, drug combination with benznidazole and long-term administration in T. cruzi-infected mice. Results Although less susceptible to Cpd1 than amastigotes, trypomastigotes present an impaired capacity to successfully establish intracellular infection of cardiac cultures. Combination of benznidazole with Cpd1 indicated no interaction (additive effect) (FIC index = 0.72) while administration to mice at one-tenth of the optimal dose (2.5 mg/kg and 10 mg/kg for Cpd1 and benznidazole, respectively) suppressed parasitaemia but failed to avoid mortality. Long-term treatment (60 days) gave a rapid drop of the parasitaemia (>98% decline) and 100% mice survival but only 16% cure. In vitro washout experiments demonstrated that although parasite release into the supernatant of infected cardiac cultures was reduced by >94%, parasite recrudescence did occur after treatment. Conclusions Parasite recrudescence did occur after treatment corroborating the hypothesis of therapeutic failure due to subpopulations of dormant forms and/or genetic factors in persister parasites involved in natural drug resistance.
  • Data de criação/publicação: 2021
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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