Chagas disease is a neglected tropical disease (NTD) caused by Trypanosoma cruzi , this protozoan is transmitted by kissing bug. Two nitroheterocyclic drugs available for the treatment of chagas disease are not only resistance but also parade toxicity effect. Therefore, this study investigates the inhibitory activity of bioactive compounds from Moringa spp against 14-α-demethylase protease of T. cruzi through e-pharmacophore and QSAR models with molecular docking and pharmacokinetic studies using Schrödinger suite. The density functional theory (DFT) of the lead compounds was performed by Spatan 10. From the pharmacophore model and ADME analysis, eight active molecules were obtained which showed high binding affinity and better interaction with the target compared with the reference ligand (Benznidazole). AutoQSAR was employed to build a model for the prediction of the compounds bioactivities with the eight compounds showing better inhibitory pIC50 comparable with the reference ligand against 14-α-demethylase protease. The results of the frontier molecular orbitals of the lead molecules revealed that the E HOMO values of the lead compounds range from -6.70 to -5.41 eV predicting the lead compounds as electron donator. Overall, this study predicted isorhamnetin, kaemferide, rhamnetin, niaziminin, aurantiamide acetate, niazirinin, eugenol and sinapic acid as inhibitors of 14-α-demethylase protease. Hence, further in vitro and in vivo experiments are suggested to ascertain the therapeutic potential of these compounds in the treatment of chagas disease. 

Exploring Molecular Docking with E-Pharmacophore and QSAR models to Predict Potent Inhibitors of 14-α-demethylase protease from Moringa spp

Based on the bidirectional interactions between neurology and cancer science, the burgeoning field “cancer neuroscience” has been proposed. An important node in the communications between nerves and cancer is the innervated niche, which has physical contact with the cancer parenchyma or nerve located in the proximity of the tumor. In the innervated niche, autophagy has recently been reported to be a double-edged sword that plays a significant role in maintaining homeostasis. Therefore, regulating the innervated niche by targeting the autophagy pathway may represent a novel therapeutic strategy for cancer treatment. Drug repurposing has received considerable attention for its advantages in cost-effectiveness and safety. The utilization of existing drugs that potentially regulate the innervated niche via the autophagy pathway is therefore a promising pharmacological approach for clinical practice and treatment selection in cancer neuroscience. Herein, we present the cancer neuroscience landscape with an emphasis on the crosstalk between the innervated niche and autophagy, while also summarizing the underlying mechanisms of candidate drugs in modulating the autophagy pathway. This review provides a strong rationale for drug repurposing in cancer treatment from the viewpoint of the autophagy-mediated innervated niche.

Drug repurposing in cancer neuroscience: From the viewpoint of the autophagy-mediated innervated niche

Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, is an important public health problem mainly in Latin America, leading to approximately 12,000 annual deaths. Current etiological treatment for CD is limited to two nitro compounds, benznidazole (Bz) and nifurtimox (Nif), both presenting relevant limitations. Different approaches have been employed to establish more effective and safer schemes to treat T. cruzi infection, mostly based on drug repurposing and combination therapies. Amiodarone (AMD), an antiarrhythmic medicament of choice for patients with the chronic cardiac form of CD, is also recognized as a trypanocidal agent. Therefore, our aim is to investigate the combined treatment Bz + AMD on trypomastigote viability, control of T. cruzi intracellular form proliferation, and recovery of the infection-induced cytoskeleton alterations in cardiac cells. The combination of Bz + AMD did not improve the direct trypanocidal effect of AMD on the infective blood trypomastigote and replicative intracellular forms of the parasite. Otherwise, the treatment of T. cruzi-infected cardiac cells with Bz plus AMD attenuated the infection-triggered cytoskeleton damage of host cells and the cytotoxic effects of AMD. Thus, the combined treatment Bz + AMD may favor parasite control and hamper tissue damage.

/pdf/benznidazole-and-amiodarone-combined-treatment-attenuates-15di4x1y.pdf

Benznidazole and amiodarone combined treatment attenuates cytoskeletal damage in Trypanosoma cruzi-infected cardiac cells

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a major neglected disease endemic to Latin America, associated to significant morbimortality comprising a remarkable socioeconomic problem mainly for low-income tropical populations. The present chapter focuses translational research on Chagas disease, approaching drug combinations and repositioning, particularly exploiting the parasite oxidative stress by prospecting prooxidant compounds combined with antagonists of antioxidant systems, for developing low-cost and safe therapies for this infection. The pertinent literature on protozoal parasitic diseases is reviewed as well as on repurposing disulfiram aiming the combination with the Chagas disease drug of choice benznidazole. Both disulfiram and its first derivative sodium diethyldithiocarbamate (DETC) are able not only to inhibit p-glycoprotein, possibly reverting resistance phenotypes, but also to reduce toxicity of numerous other drugs, heavy metals, etc. Therefore, this innovation, presently in clinical research, may furnish a novel therapeutic for T. cruzi infections overcoming the adverse effects and refractory cases that impair the effectiveness of Chagas disease treatment. 

Translational Research on Chagas Disease: Focusing on Drug Combination and Repositioning

Pathogenic protists are a group of organisms responsible for causing a variety of human diseases including malaria, sleeping sickness, Chagas disease, leishmaniasis, and toxoplasmosis, among others. These diseases, which affect more than one billion people globally, mainly the poorest populations, are characterized by severe chronic stages and the lack of effective antiparasitic treatment. Parasitic protists display complex life-cycles and go through different cellular transformations in order to adapt to the different hosts they live in. Autophagy, a highly conserved cellular degradation process, has emerged as a key mechanism required for these differentiation processes, as well as other functions that are crucial to parasite fitness. In contrast to yeasts and mammals, protist autophagy is characterized by a modest number of conserved autophagy-related proteins (ATGs) that, even though, can drive the autophagosome formation and degradation. In addition, during their intracellular cycle, the interaction of these pathogens with the host autophagy system plays a crucial role resulting in a beneficial or harmful effect that is important for the outcome of the infection. In this review, we summarize the current state of knowledge on autophagy and other related mechanisms in pathogenic protists and their hosts. We sought to emphasize when, how, and why this process takes place, and the effects it may have on the parasitic cycle. A better understanding of the significance of autophagy for the protist life-cycle will potentially be helpful to design novel anti-parasitic strategies.

Autophagy in protists and their hosts: When, how and why?

T. cruzi, the causal agent of Chagas disease, is a parasite able to infect different types of host cells and to persist chronically in the tissues of human and animal hosts. These qualities and the lack of an effective treatment for the chronic stage of the disease have contributed to the durability and the spread of the disease around the world. There is an urgent necessity to find new therapies for Chagas disease. Drug repurposing is a promising and cost-saving strategy for finding new drugs for different illnesses. In this work we describe the effect of carvedilol on T. cruzi. This compound, selected by virtual screening, increased the accumulation of immature autophagosomes characterized by lower acidity and hydrolytic properties. As a consequence of this action, the survival of trypomastigotes and the replication of epimastigotes and amastigotes were impaired, resulting in a significant reduction of infection and parasite load. Furthermore, carvedilol reduced the whole-body parasite burden peak in infected mice. In summary, in this work we present a repurposed drug with a significant in vitro and in vivo activity against T. cruzi. These data in addition to other pharmacological properties make carvedilol an attractive lead for Chagas disease treatment.

/pdf/repurposing-carvedilol-as-a-novel-inhibitor-of-the-8rbkpfufsp.pdf

Cynthia Vanesa Rivero

Papers

Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival.