scholarly journals Cruzain Inhibitors as Prominent Molecules with The Potential to become Drug Candidates against Chagas Disease

2019 ◽  
Vol 2 (3) ◽  
2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.


2021 ◽  
Vol 9 ◽  
Author(s):  
Brindha J ◽  
Balamurali M. M ◽  
Kaushik Chanda

Neglected tropical diseases (NTDs) as termed by WHO include twenty different infectious diseases that are caused by bacteria, viruses, and parasites. Among these NTDs, Chagas disease and leishmaniasis are reported to cause high mortality in humans and are further associated with the limitations of existing drugs like severe toxicity and drug resistance. The above hitches have rendered researchers to focus on developing alternatives and novel therapeutics for the treatment of these diseases. In the past decade, several target-based drugs have emerged, which focus on specific biochemical pathways of the causative parasites. For leishmaniasis, the targets such as nucleoside analogs, inhibitors targeting nucleoside phosphate kinases of the parasite’s purine salvage pathway, 20S proteasome of Leishmania, mitochondria, and the associated proteins are reviewed along with the chemical structures of potential drug candidates. Similarly, in case of therapeutics for Chagas disease, several target-based drug candidates targeting sterol biosynthetic pathway (C14-ademethylase), L-cysteine protease, heme peroxidation, mitochondria, farnesyl pyrophosphate, etc., which are vital and unique to the causative parasite are discussed. Moreover, the use of nano-based formulations towards the therapeutics of the above diseases is also discussed.


2010 ◽  
Vol 53 (4) ◽  
pp. 1763-1773 ◽  
Author(s):  
Katrien Brak ◽  
Iain D. Kerr ◽  
Kimberly T. Barrett ◽  
Nobuhiro Fuchi ◽  
Moumita Debnath ◽  
...  

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Rafael Obata Trevisan ◽  
Malú Mateus Santos ◽  
Chamberttan Souza Desidério ◽  
Leandro Gomes Alves ◽  
Thiago de Jesus Sousa ◽  
...  

Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Despite the efforts and distinct methodologies, the search of antigens for diagnosis, vaccine, and drug targets for the disease is still needed. The present study is aimed at identifying possible antigens that could be used for diagnosis, vaccine, and drugs targets against T. cruzi using reverse vaccinology and molecular docking. The genomes of 28 T. cruzi strains available in GenBank (NCBI) were used to obtain the genomic core. Then, subtractive genomics was carried out to identify nonhomologous genes to the host in the core. A total of 2630 conserved proteins in 28 strains of T. cruzi were predicted using OrthoFinder and Diamond software, in which 515 showed no homology to the human host. These proteins were evaluated for their subcellular localization, from which 214 are cytoplasmic and 117 are secreted or present in the plasma membrane. To identify the antigens for diagnosis and vaccine targets, we used the VaxiJen software, and 14 nonhomologous proteins were selected showing high binding efficiency with MHC I and MHC II with potential for in vitro and in vivo tests. When these 14 nonhomologous molecules were compared against other trypanosomatids, it was found that the retrotransposon hot spot (RHS) protein is specific only for T. cruzi parasite suggesting that it could be used for Chagas diagnosis. Such 14 proteins were analyzed using the IEDB software to predict their epitopes in both B and T lymphocytes. Furthermore, molecular docking analysis was performed using the software MHOLline. As a result, we identified 6 possible T. cruzi drug targets that could interact with 4 compounds already known as antiparasitic activities. These 14 protein targets, along with 6 potential drug candidates, can be further validated in future studies, in vivo, regarding Chagas disease.


2015 ◽  
Vol 59 (10) ◽  
pp. 6385-6394 ◽  
Author(s):  
Shilpi Khare ◽  
Xianzhong Liu ◽  
Monique Stinson ◽  
Ianne Rivera ◽  
Todd Groessl ◽  
...  

ABSTRACTTwo CYP51 inhibitors, posaconazole and the ravuconazole prodrug E1224, were recently tested in clinical trials for efficacy in indeterminate Chagas disease. The results from these studies show that both drugs cleared parasites from the blood of infected patients at the end of the treatment but that parasitemia rebounded over the following months. In the current study, we sought to identify a dosing regimen of posaconazole that could permanently clearTrypanosoma cruzifrom mice with experimental Chagas disease. Infected mice were treated with posaconazole or benznidazole, an established Chagas disease drug, and parasitological cure was defined as an absence of parasitemia recrudescence after immunosuppression. Twenty-day therapy with benznidazole (10 to 100 mg/kg of body weight/day) resulted in a dose-dependent increase in antiparasitic activity, and the 100-mg/kg regimen effected parasitological cure in all treated mice. In contrast, all mice remained infected after a 25-day treatment with posaconazole at all tested doses (10 to 100 mg/kg/day). Further extension of posaconazole therapy to 40 days resulted in only a marginal improvement of treatment outcome. We also observed similar differences in antiparasitic activity between benznidazole and posaconazole in acuteT. cruziheart infections. While benznidazole induced rapid, dose-dependent reductions in heart parasite burdens, the antiparasitic activity of posaconazole plateaued at low doses (3 to 10 mg/kg/day) despite increasing drug exposure in plasma. These observations are in good agreement with the outcomes of recent phase 2 trials with posaconazole and suggest that the efficacy models combined with the pharmacokinetic analysis employed here will be useful in predicting clinical outcomes of new drug candidates.


2020 ◽  
Author(s):  
Jose G. Rosas-Jimenez ◽  
Marco A. Garcia-Revilla ◽  
Abraham Madariaga-Mazon ◽  
Karina Martinez-Mayorga

AbstractChagas disease affects 8–11 million people worldwide, most of them living in Latin America. Moreover, migratory phenomenon have spread the infection beyond endemic areas. Efforts for the development of new pharmacological therapies are paramount, as the pharmacological profile of the two marketed drugs currently available, nifurtimox and benznidazole, needs to be improved. Cruzain, a parasitic cysteine protease, is one of the most attractive biological targets due to its roles in parasite survival and immune evasion. In this work, we generated Quantitative Structure-Activity Relationship linear models for the prediction of pIC50 values of cruzain inhibitors. The statistical parameters for internal and external validation indicate high predictability with a cross-validated correlation coefficient of and an external correlation coefficient of . The applicability domain is quantitatively defined, according to QSAR good practices, using the leverage method. A qualitative interpretation of the model is provided based on protein-ligand interactions obtained from docking studies and structural information codified in the molecular descriptors relevant to the QSAR model. The model described in this work will be valuable for the discovery of novel cruzain inhibitors.Author summaryChagas disease is a major health problem in Latin America. The disease involves a long-lasting silent phase that usually culminates in serious or fatal heart damage. Despite its prevalence, there are only two antichagas approved drugs available. Despite these drugs have been in the market for more than 50 years, significant undesirable side effects and modest effectiveness in the chronic phase are prevalent. The need of new drugs to treat this disease is evident. Cruzain is a vital protein for the survival of Trypanosoma cruzi, the parasite causative of Chagas disease. Inhibition of this species-specific protein has been associated with improvements in pharmacological effects in animal models. Thus, blocking the activity of cruzain is an attractive approach for the development of antichagas agents. In this work, we present a validated mathematical model capable of predicting the cruzain inhibition value of a molecule from its chemical structure. This model can contribute to the identification of potential pharmacological alternatives against Chagas disease.


2015 ◽  
Vol 59 (12) ◽  
pp. 7564-7570 ◽  
Author(s):  
F. H. Guedes-da-Silva ◽  
D. G. J. Batista ◽  
C. F. da Silva ◽  
M. B. Meuser ◽  
M. R. Simões-Silva ◽  
...  

ABSTRACTThe lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimentalT. cruziCYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps ofin vivotrials of novel anti-T. cruzidrug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates forin vivoassays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD.


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