Review on Experimental Treatment Strategies Against Trypanosoma cruzi

Mazzeti, Ana Lia; Capelari-Oliveira, Patricia; Bahia, Maria Terezinha; Mosqueira, Vanessa Carla Furtado

doi:10.2147/jep.s267378

Cited by 37 publications

(22 citation statements)

References 217 publications

(430 reference statements)

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“… 40 However, no novel chemical entity has yet been discovered or implemented for this silent disease although some pre-clinical studies have reported promising drug candidates for CD, including nucleoside derivatives that act on the purine salvage pathway. 41 Our group reassessed the natural antibiotic tubercidin and a series of 7-substituted analogues aiming to identify novel hits against Trypanosoma brucei , the agent of human African trypanosomiasis. 42 Besides being very active against T. brucei , some phenyl-substituted analogues also presented high in vitro potency against T. cruzi , which motivated us to explore related 7-substituted 7-deazapurine moieties with the carbohydrate group of cordycepin (i.e.…”

Section: Discussionmentioning

confidence: 99%

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

Cardoso-Santos

Fiuza

Silva

et al. 2021

JAC-Antimicrobial Resistance

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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-β-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.

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Section: Discussionmentioning

confidence: 99%

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

Cardoso-Santos

Fiuza

Silva

et al. 2021

JAC-Antimicrobial Resistance

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“…The strategy of repurposing drugs has been used as a fast alternative for different neglected diseases [ 4 , 23 , 46 ]. Previous data has shown a high TMX in vitro activity (IC 50 2.4 µM) against amastigotes and promastigotes of Leishmania and in vivo efficacy at doses of 20 mg/kg in infected-mice and hamsters [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Repositioning of Tamoxifen in Surface-Modified Nanocapsules as a Promising Oral Treatment for Visceral Leishmaniasis

et al. 2021

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Standards of care for human visceral leishmaniasis (VL) are based on drugs used parenterally, and oral treatment options are urgently needed. In the present study, a repurposing strategy was used associating tamoxifen (TMX) with polyethylene glycol-block-polylactide nanocapsules (NC) and its anti-leishmanial efficacy was reported in vivo. Stable surface modified-NC (5 mg/mL of TMX) exhibited 200 nm in size, +42 mV of zeta potential, and 98% encapsulation efficiency. Atomic force microscopy evidenced core-shell-NC. Treatment with TMX-NC reduced parasite-DNA quantified in liver and spleen compared to free-TMX; and provided a similar reduction of parasite burden compared with meglumine antimoniate in mice and hamster models. Image-guided biodistribution showed accumulation of NC in liver and spleen after 30 min post-administration. TMX-NC reduced the number of liver granulomas and restored the aspect of capsules and trabeculae in the spleen of infected animals. TMX-NC was tested for the first time against VL models, indicating a promising formulation for oral treatment.

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“…Despite the efforts to discover novel and safe drugs, anti- T. cruzi chemotherapy for both newborns and adults still relies on nifurtimox (NFX) and benznidazole (BZN), two drugs discovered in the '60s with known adverse side effects ( 64 , 66 ). To improve CD treatment, strategies based on combinations of existing drugs or re-dosing regimens are currently being evaluated ( 67 ). Even though the excellent efficacy in reducing the parasitaemia when administered during the acute phase, CD treatment is less effective in preventing the clinical progression when given long time after the initial infection, suggesting a role for the host immune response ( 68 ).…”

Section: Chagas Diseasementioning

confidence: 99%

Monoclonal Antibodies for Protozoan Infections: A Future Reality or a Utopic Idea?

et al. 2021

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Following the SARS-CoV-2 pandemic, several clinical trials have been approved for the investigation of the possible use of mAbs, supporting the potential of this technology as a therapeutic approach for infectious diseases. The first monoclonal antibody (mAb), Muromonab CD3, was introduced for the prevention of kidney transplant rejection more than 30 years ago; since then more than 100 mAbs have been approved for therapeutic purposes. Nonetheless, only four mAbs are currently employed for infectious diseases: Palivizumab, for the prevention of respiratory syncytial virus (RSV) infections, Raxibacumab and Obiltoxaximab, for the prophylaxis and treatment against anthrax toxin and Bezlotoxumab, for the prevention of Clostridium difficile recurrence. Protozoan infections are often neglected diseases for which effective and safe chemotherapies are generally missing. In this context, drug resistance and drug toxicity are two crucial problems. The recent advances in bioinformatics, parasite genomics, and biochemistry methodologies are contributing to better understand parasite biology, which is essential to guide the development of new therapies. In this review, we present the efforts that are being made in the evaluation of mAbs for the prevention or treatment of leishmaniasis, Chagas disease, malaria, and toxoplasmosis. Particular emphasis will be placed on the potential strengths and weaknesses of biological treatments in the control of these protozoan diseases that are still affecting hundreds of thousands of people worldwide.

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Review on Experimental Treatment Strategies Against Trypanosoma cruzi

Cited by 37 publications

References 217 publications

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

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

Repositioning of Tamoxifen in Surface-Modified Nanocapsules as a Promising Oral Treatment for Visceral Leishmaniasis

Monoclonal Antibodies for Protozoan Infections: A Future Reality or a Utopic Idea?

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