@misc{10481/80513,
year = {2023},
month = {1},
url = {https://hdl.handle.net/10481/80513},
abstract = {Introduction: Chagas disease is caused by the protozoan parasite
Trypanosoma cruzi, and it is the most important neglected tropical disease in
the Americas. Two drugs are available to treat the infection, but their efficacy in
the chronic stage of the disease, when most cases are diagnosed, is reduced.
Their tolerability is also hindered by common adverse effects, making the
development of safer and efficacious alternatives a pressing need. T. cruzi is
unable to synthesize purines de novo, relying on a purine salvage pathway to
acquire these from its host, making it an attractive target for the development
of new drugs.
Methods: We evaluated the anti-parasitic activity of 23 purine analogs with
different substitutions in the complementary chains of their purine rings. We
sequentially screened the compounds' capacity to inhibit parasite growth, their
toxicity in Vero and HepG2 cells, and their specific capacity to inhibit the
development of amastigotes. We then used in-silico docking to identify their
likely targets. Results: Eight compounds showed specific anti-parasitic activity, with IC50
values ranging from 2.42 to 8.16 mM. Adenine phosphoribosyl transferase, and
hypoxanthine-guanine phosphoribosyl transferase, are their most likely targets.
Discussion: Our results illustrate the potential role of the purine salvage pathway
as a target route for the development of alternative treatments against T. cruzi
infection, highlithing the apparent importance of specific substitutions, like the
presence of benzene groups in the C8 position of the purine ring, consistently
associated with a high and specific anti-parasitic activity.},
organization = {Generalitat of Catalonia Universities and Research Department, Spain	2017SGR00924},
organization = {Carlos III Health Institute (ISCIII), RICET Network for Cooperative Research in Tropical Diseases (ISCIII)	RD16/0027/0004},
organization = {European Commission},
organization = {ISCIII project	PI18/01054},
organization = {Spanish Ministry of Science, Innovation, and Universities through the "Centro de Excelencia Severo Ochoa	2019-2023''
CEX2018-000
806-S},
organization = {Generalitat of Catalonia through the "CERCA Program},
organization = {La Caixa Foundation	100010434
LCF/BQ/DI21/11860037},
publisher = {Frontiers},
keywords = {Chagas disease},
keywords = {Trypanosoma cruzi},
keywords = {Purine derivatives},
keywords = {Antiparasitic assays},
keywords = {Cytotoxicity assays},
keywords = {Drug discovery cascade},
title = {Identification of compounds with activity against Trypanosoma cruzi within a collection of synthetic nucleoside analogs},
doi = {10.3389/fcimb.2022.1067461},
author = {Barnadas Carceller, Berta and Córdoba Gómez, Laura and Díaz Mochón, Juan José and Molina Pineda Infantas, Ignacio Jesús and Pineda De Las Infant Y Villatoro, María José},
}