Identification of compounds with activity against Trypanosoma cruzi within a collection of synthetic nucleoside analogs

Abstract

IntroductionChagas 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. MethodsWe 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.ResultsEight compounds showed specific anti-parasitic activity, with IC50 values ranging from 2.42 to 8.16 μM. Adenine phosphoribosyl transferase, and hypoxanthine-guanine phosphoribosyl transferase, are their most likely targets. DiscussionOur 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.

Possible Chemotherapeutic Potential of Inhibiting N-Alpha Terminal Acetylation Activities to Combat Trypanosome Infections

“…The efforts to find new drug targets against trypanosome infections are advancing, notably interference with the trypanothione metabolism pathway [142], calcium homeostasis, nucleoside analog targeting purine salvage pathway, and drug combination of low-cost molecules in T. cruzi [143,144]. Furthermore, it is now possible to perform in silico analysis to identify new drug targets in trypanosomes [14,145].…”

Using 5-Nitroimidazole Derivatives against Neglected Tropical Protozoan Diseases: Systematic Review

“…Fexinidazole (FXZ) (51) has demonstrated activity against several strains of T. cruzi (CL Brener, Y, Colombian, and VL-10). Experiments have also been conducted on infected mice to compare its efficacy to that of BNZ.…”

“…Furthermore, mice infected with BNZ-resistant Patients treated with BNZ or NFX present adverse effects such as fever, nausea, headaches, muscle and joint pains, neurological reactions (restlessness, disorientation, amnesia, insomnia, spasms, paresthesias, polyneuritis, and seizures), dermatological manifestations (dermatitis with skin rashes, generalized or peritoneal edema), and bone marrow depression (lymphadenopathy, agranulocytosis, neutropenia, and thrombocytopenic purpura), and BNZ and NFX are also considered genotoxic, carcinogenic, and teratogenic [49,50]. Additionally, the pharmacological administration of BNZ or NFX occurs over an extended period of 60 to 90 days [51].…”

Genome-wide screens connect HD82 loss-of-function to purine analog resistance in African trypanosomes

“…The African trypanosome, Trypanosoma brucei , is a protozoan parasite that causes devastating diseases in both humans and animals, while related trypanosomatids cause other devastating and neglected tropical diseases ( 1 ). There has been substantial recent interest in developing nucleoside analogs as anti-trypanosomal therapeutics ( 2 – 8 ), specifically because trypanosomatids, unlike their mammalian hosts, lack the capacity for de novo purine biosynthesis ( 5 ). Consequently, trypanosomatids are purine auxotrophs that, being incapable of de novo purine synthesis, salvage purines from their hosts, for the biosynthesis of nucleic acids.…”