JVG9, a benzimidazole derivative, alters the surface and cytoskeleton of Trypanosoma cruzi bloodstream trypomastigotes

Díaz-Chiguer, Dylan L.; Hernández‐Luis, Francisco; Nogueda‐Torres, Benjamín; Castillo, Rafael; Reynoso-Ducoing, Olivia; Hernández‐Campos, Alicia; Ambrosio, Javier R.

doi:10.1590/0074-0276140096

Cited by 11 publications

(3 citation statements)

References 19 publications

(28 reference statements)

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“…In this context, benzimidazole derivatives synthetized by our group have shown biological activity against several parasites [ 31 , 32 , 33 , 34 , 35 ], and some of them have shown inactivation of Trypanosoma cruzi TIM (TcTIM) [ 36 , 37 , 38 ]. In the present work, we searched TbTIM inactivators from our in house library of benzimidazole derivatives.…”

Section: Introductionmentioning

confidence: 99%

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies

et al. 2017

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Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei. Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1, 2 and 3) with an I50 value of 84, 82 and 73 µM, respectively. Kinetic analyses indicated that the three molecules were selective when tested against human TIM (HsTIM) activity. Additionally, to study their binding mode in TbTIM, we performed a 100 ns molecular dynamics simulation of TbTIM-inactivator complexes. Simulations showed that the binding of compounds disturbs the structure of the protein, affecting the conformations of important domains such as loop 6 and loop 8. In addition, the physicochemical and drug-like parameters showed by the three compounds suggest a good oral absorption. In conclusion, these molecules will serve as a guide to design more potent inactivators that could be used to obtain new drugs against HAT.

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Section: Introductionmentioning

confidence: 99%

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies

et al. 2017

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“…In vivo short-term evaluation of the trypanocidal activity of the FDA-approved drugs. Six groups of six CD1 female mice were infected with blood trypomastigotes of Ninoa and INC-5 strains following the methodology previously described in Romanha et al [ 111 ] and in Díaz-Chiguer et al [ 112 ]. At day 13 post-infection, when the infected mice reached an average of 5 × 10 6 parasites/mL, a single dose of the FDA-approved drugs at 100 mg/kg body weight was orally administered.…”

Section: Methodsmentioning

confidence: 99%

Repositioned Drugs for Chagas Disease Unveiled via Structure-Based Drug Repositioning

Adasme

Bolz

Adelmann

et al. 2020

IJMS

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Chagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people in South America. The current treatments are limited, have severe side effects, and are only partially effective. Drug repositioning, defined as finding new indications for already approved drugs, has the potential to provide new therapeutic options for Chagas. In this work, we conducted a structure-based drug repositioning approach with over 130,000 3D protein structures to identify drugs that bind therapeutic Chagas targets and thus represent potential new Chagas treatments. The screening yielded over 500 molecules as hits, out of which 38 drugs were prioritized following a rigorous filtering process. About half of the latter were already known to have trypanocidal activity, while the others are novel to Chagas disease. Three of the new drug candidates—ciprofloxacin, naproxen, and folic acid—showed a growth inhibitory activity in the micromolar range when tested ex vivo on T. cruzi trypomastigotes, validating the prediction. We show that our drug repositioning approach is able to pinpoint relevant drug candidates at a fraction of the time and cost of a conventional screening. Furthermore, our results demonstrate the power and potential of structure-based drug repositioning in the context of neglected tropical diseases where the pharmaceutical industry has little financial interest in the development of new drugs.

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“…Alterations in the plasma membrane are usually related on T. cruzi under treatment with different drugs due to the osmotic stress unleashed or the attempt of the parasite to promote the shedding of the compound. 37 , 38 Interestingly, several studies using human and murine cell models demonstrated that HIV-IPs extensively affect the mitochondrion and the endoplasmic reticulum. Misbalance in these organelles are directly associated with lipid disturbances induced by HIV-PIs in HIV-positive patients.…”

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Repositioning drug strategy against Trypanosoma cruzi: lessons learned from HIV aspartyl peptidase inhibitors

Sangenito

d’Avila-Levy

Branquinha

et al. 2022

Mem. Inst. Oswaldo Cruz

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Chagas disease (CD) is an old neglected problem that affects more than 6 million people through 21 endemic countries in Latin America. Despite being responsible for more than 12 thousand deaths per year, the disease disposes basically of two drugs for its treatment, the nitroimidazole benznidazole and the nitrofuran nifurtimox. However, these drugs have innumerous limitations that greatly reduce the chances of cure. In Brazil, for example, only benznidazole is available to treat CD patients. Therefore, some proof-of-concept phase II clinical trials focused on improving the current treatment with benznidazole, also comparing it with repositioned drugs or combining them. Indeed, repositioning already marketed drugs in view of combating neglected tropical diseases is a very interesting approach in the context of decreased time for approval, better treatment options and low cost for development and implementation. After the introduction of human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) in the treatment of acquired immune deficiency syndrome (AIDS), the prevalence and incidence of parasitic, fungal and bacterial co-infections suffered a marked reduction, making these HIV-PIs attractive for drug repositioning. In this line, the present perspective presents the promising and beneficial data concerning the effects of HIV-PIs on the clinically relevant forms of Trypanosoma cruzi (i.e., trypomastigotes and amastigotes) and also highlights the ultrastructural and physiological targets for the HIV-PIs on this parasite. Therefore, we raise the possibility that HIV-PIs could be considered as alternative treatment options in the struggle against CD.

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JVG9, a benzimidazole derivative, alters the surface and cytoskeleton of Trypanosoma cruzi bloodstream trypomastigotes

Cited by 11 publications

References 19 publications

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies

Repositioned Drugs for Chagas Disease Unveiled via Structure-Based Drug Repositioning

Repositioning drug strategy against Trypanosoma cruzi: lessons learned from HIV aspartyl peptidase inhibitors

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