Repositioning FDA-Approved Drug Against Chagas Disease and Cutaneous Leishmaniosis by Structure-Based Virtual Screening.

BACKGROUND: Chagas disease and cutaneous leishmaniasis, two parasitic diseases caused by Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana), respectively, have a major global impact. Current pharmacological treatments for these diseases are limited and can cause severe side effects; thus, there is a need for new antiprotozoal drugs. METHODS: Using molecular docking, this work describes a structure-based virtual screening of an FDA-approved drug library against Trypanosoma cruzi and Leishmania mexicana glycolytic enzyme triosephosphate isomerase (TIM), which is highly conserved in these parasites. The selected compounds with potential dual inhibitory activity were tested in vitro to confirm their biological activity. RESULTS: The study showed that five compounds: nilotinib, chlorhexidine, protriptyline, cyproheptadine, and montelukast, were more active against T. cruzi, than the reference drugs, nifurtimox and benznidazole while chlorhexidine and protriptyline were the most active against L. mexicana. CONCLUSIONS: The analysis of these compounds and their structural characteristics may provide the basis for the development of new antiprotozoal agents.

Relevance of Helminth-Microbiota interplay in the host immune response.

Helminths have been present throughout the evolution of humans, promoting the development and maturation of the host immune system. However, this interaction is not exclusive between these two organisms, as the microbiota is also involved in this human evolutionary process and maintains a balanced relationship inside the host. Consequently, helminths have been forced to interact and co-evolve with the microbiota, shaping microbial communities and allowing the development of reciprocal mechanisms that favour their establishment. This helminth-microbiota association, in turn, induced the activation of different host immunoregulatory pathways to preserve health by preventing the development of some diseases associated with inflammatory immune responses. Unfortunately, this collaborative relationship can be quali- and quantitatively altered by the diet and the use of antibacterial and antihelminthic drugs. Understanding the mechanisms involved in this complex three-way communication that has continued for many years is crucial for preserving health and for the generation of new therapeutic alternatives.

Fasciola hepatica-derived molecules as potential immunomodulators.

Through the years, helminths have co-existed with many species. This process has allowed parasites to live within them for long periods and, in some cases, to generate offspring. In particular, this ability has allowed Fasciola hepatica to survive the diverse immunological responses faced within its wide range of hosts. The vast repertoire of molecules that are constantly secreted in large quantities by the parasite, acts directly on several cells of the immune system affecting their antiparasitic capacities. Interestingly, these molecules can direct the host immune response to an anti-inflammatory and regulatory phenotype that assures the survival of the parasite with less harm to the host. Based on these observations, some of the products of F. hepatica, as well as those of other helminths, have been studied, either as a total extract, extracellular vesicles or as purified molecules, to establish and characterize their anti-inflammatory mechanisms. Until now, the results obtained encourage further research directed to discover new helminth-derived alternatives to replace current therapies, which can be useful for people suffering from inflammatory diseases like autoimmunity or allergy processes that affect their life quality. In this review, some of the most studied molecules derived from F. hepatica and their modulating capacities are discussed.