Trypanosoma cruzi (T. cruzi) is a parasite that affects humans and other mammals. T. cruzi depends on glycolysis as a source of adenosine triphosphate (ATP) supply, and triosephosphate isomerase (TIM) plays a key role in this metabolic pathway. This enzyme is an attractive target for the design of new trypanocidal drugs. In this study, a ligand-based virtual screening (LBVS) from the ZINC15 database using benzimidazole as a scaffold was accomplished. Later, a molecular docking on the interface of T. cruzi TIM (TcTIM) was performed and the compounds were grouped by interaction profiles. Subsequently, a selection of compounds was made based on cost and availability for in vitro evaluation against blood trypomastigotes. Finally, the compounds were analyzed by molecular dynamics simulation, and physicochemical and pharmacokinetic properties were determined using SwissADME software. A total of 1604 molecules were obtained as potential TcTIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC₅₀) values of 155.86 and 226.30 µM, respectively. Molecular docking and molecular dynamics simulation analyzes showed a favorable docking score of BP5 compound on TcTIM. Additionally, BP5 showed a low docking score (−5.9 Kcal/mol) on human TIM compared to the control ligand (−7.2 Kcal/mol). Both compounds BP2 and BP5 showed good physicochemical and pharmacokinetic properties as new anti-T. cruzi agents.

Protozoan parasite diseases cause significant mortality and morbidity worldwide. Factors such as climate change, extreme poverty, migration, and a lack of life opportunities lead to the propagation of diseases classified as tropical or non-endemic. Although there are several drugs to combat parasitic diseases, strains resistant to routinely used drugs have been reported. In addition, many first-line drugs have adverse effects ranging from mild to severe, including potential carcinogenic effects. Therefore, new lead compounds are needed to combat these parasites. Although little has been studied regarding the epigenetic mechanisms in lower eukaryotes, it is believed that epigenetics plays an essential role in vital aspects of the organism, from controlling the life cycle to the expression of genes involved in pathogenicity. Therefore, using epigenetic targets to combat these parasites is foreseen as an area with great potential for development. This review summarizes the main known epigenetic mechanisms and their potential as therapeutics for a group of medically important protozoal parasites. Different epigenetic mechanisms are discussed, highlighting those that can be used for drug repositioning, such as histone post-translational modifications (HPTMs). Exclusive parasite targets are also emphasized, including the base J and DNA 6 mA. These two categories have the greatest potential for developing drugs to treat or eradicate these diseases.

Giardia lamblia (G. lamblia) is the main causative agent of diarrhea worldwide, affecting children and adults alike; in the former, it can be lethal, and in the latter a strong cause of morbidity. Despite being considered a predominant disease in low-income and developing countries, current migratory flows have caused an increase in giardiasis cases in high-income countries. Currently, there is a wide variety of chemotherapeutic treatments to combat this parasitosis, most of which have potentially serious side effects, such as genotoxic, carcinogenic, and teratogenic. The necessity to create novel treatments and discover new therapeutic targets to fight against this illness is evident. The current review centers around the controversial nucleolus of G. lamblia, providing a historical perspective that traces its apparent absence to the present evidence supporting its existence as a subnuclear compartment in this organism. Additionally, possible examples of ncRNAs and proteins ubiquitous to the nucleolus that can be used as targets of different therapeutic strategies are discussed. Finally, some examples of drugs under research that could be effective against G. lamblia are described.

Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist Giardia lamblia, which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Giardia lamblia. Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.

Malaria has been one of the most lethal infectious diseases throughout history, claiming a high number of human lives. The genomic plasticity of Plasmodium falciparum, the causative agent of the most severe and deadly form of malaria, gives the parasite a constant resistance to drugs developed for its control. Despite efforts to control and even eradicate the disease, these have largely been unsuccessful due to the parasite's continuous adaptations. This study aims to examine the key genes involved in parasite resistance and propose a shift in the combat strategy. Gene silencing techniques offer promise in combating malaria, yet further research is needed to harness their potential for disease control fully. Although there is still a long way to go for the implementation of gene silencing-based therapeutic strategies, this review addresses examples of the use of such techniques in various human diseases and how they could be extrapolated for malaria treatment.

Background: Parasitic diseases, particularly Chagas disease caused by Trypanosoma cruzi, primarily affect developing countries but are now spreading to wealthier nations due to changing migration patterns. With approximately 8 to 9 million cases annually and a rise in drug resistance and side effects, there is an urgent need for new therapeutic approaches. Objectives: This study aimed to identify potential pharmacological compounds to target the TATA Binding Protein (TBP) of T. cruzi. Methods: Over eleven thousand FDA-approved pharmacological compounds were analyzed using in silico methods, including homology modeling, molecular docking, and molecular dynamics simulations. In addition, in vitro assays were conducted to assess the trypanocidal activity of promising candidates against T. cruzi epimastigotes and their selectivity toward macrophage J774.2. Results: Two compounds, DB00890 and DB07635, emerged as promising candidates, demonstrating significant potential against T. cruzi TBP. Compound DB00890 had trypanocidal activity against T. cruzi epimastigotes, with IC₅₀ values of 70.4 µM (SI 2.84) and 37.3 µM (SI 5.36) for the NINOA and A1 strains, respectively. Conclusions: Our findings suggest DB00890 is a promising candidate for the development of new agents against Chagas disease, with the potential for targeted therapies that minimize side effects. These results provide a strong foundation for further research into novel treatments for parasitic diseases caused by T. cruzi.