Abstract
The protozoans Leishmania and Trypanosoma, belonging to the same Trypanosomatidae family, are the causative agents of Leishmaniasis, Chagas disease, and human African trypanosomiasis. Overall, these infections affect millions of people worldwide, posing a serious health issue as well as socio-economical concern. Current treatments are inadequate, mainly due to poor efficacy, toxicity, and emerging resistance; therefore, there is an urgent need for new drugs. Among several molecular targets proposed, trypanothione reductase (TR) is of particular interest for its critical role in controlling the parasite’s redox homeostasis and several classes of active compounds that inhibit TR have been proposed so far. This review provides a comprehensive overview of TR’s structural characterization. In particular, we discuss all the structural features of TR relevant for drug discovery, with a focus on the recent advances made in the understanding of inhibitor binding. The reported cases show how, on the basis of the detailed structural information provided by the crystallographic analysis, it is possible to rationally modify molecular scaffolds to improve their properties.
Highlights
Leishmaniasis, Chagas disease, and human African trypanosomiasis (HAT), known as sleeping sickness, are vector borne zoonosis that affect millions of people worldwide and lead to the death of about 100,000 humans per year
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Crystallographic analysis of the complex revealed that the compound binds at the entrance of NADPH site, similar to RDS777, in a pocket not conserved in human Glutathione Reductase (GR) (Figure 9)
Summary
Leishmaniasis, Chagas disease, and human African trypanosomiasis (HAT), known as sleeping sickness, are vector borne zoonosis that affect millions of people worldwide and lead to the death of about 100,000 humans per year These diseases are caused by infection with the trypanosomatids. The therapeutic arsenal currently available for these diseases includes suramin, pentamidine, melarsoprol, and eflornithine for HAT; benznidazole and nifurtimox for Chagas disease; miltefosine, amphotericin B in liposomal formulation, pentavalent antimonials, and paromomycin for visceral leishmaniasis Despite the need, these drugs are unsatisfactory because of a number of reasons: they are poorly effective, manifest severe side effects, episodes of resistance are increasingly frequent, and most treatments require prolonged and parenteral administration not suited for therapy in poor countries. As shown by some examples reported, it is possible to plan chemical modification of selected molecules in order to improve their potency and selectivity or to alter other characteristics, such as solubility, pharmacokinetics, and dynamics, without affecting affinity
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