An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases

Abstract

The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled “Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology”.

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

“…The use of the anti-inflammatory administration of aspirin does not alter the parasitological course of T. cruzi infection in mice, however reduced cardiac inflammatory infiltrates and thromboxane levels [ 151 ]. Another type of drug being developed to treat Chagas disease is the so-called target-based drugs to interfere with specific pathways of T. cruzi [ 152 ]. There are several of those; however, the most important are drugs that can target the ergosterol biosynthesis pathway, trypanothione reductase, cruzipain, enolase, ribose-5-phosphate isomerase, sterol 14- α -demethylase, pteridine reductase, farnesyl diphosphate synthase, isocitrate dehydrogenase 2, dihydrofolate reductase-thymidylate synthase, and the sirtuins [ 152 ].…”

“…Another type of drug being developed to treat Chagas disease is the so-called target-based drugs to interfere with specific pathways of T. cruzi [ 152 ]. There are several of those; however, the most important are drugs that can target the ergosterol biosynthesis pathway, trypanothione reductase, cruzipain, enolase, ribose-5-phosphate isomerase, sterol 14- α -demethylase, pteridine reductase, farnesyl diphosphate synthase, isocitrate dehydrogenase 2, dihydrofolate reductase-thymidylate synthase, and the sirtuins [ 152 ]. A schematic view of those approaches can be found in Figure 5 .…”

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

“…They are often co-endemic in certain regions of the world (Leishmaniasis and Chagas' disease in South America and Leishmaniasis and HAT in Africa) and they have span worldwide because of globalization caused by human migration. Despite being some of the most life-threatening infective diseases, only a poor and inadequate chemotherapy is available (De Rycker et al, 2018;Santos et al, 2020;Kourbeli et al, 2021). American trypanosomiasis also called Chagas' disease after its discoverer, the Brazilian scientist Carlos Chagas, is endemic in Latin America where there are 7-8 million infected people, 10,000 annual deaths and 25 million people at risk of infection.…”

“…However, most of these drugs show toxicity problems and their efficacy is variable depending on the type and stage of the disease. Although the mortality rates for HAT have decreased substantially in the last years with less than 1,000 cases found in 2019, the development of improved drugs bearing high bioavailability and low toxicity is crucial to definitively fight HAT (Nagle et al, 2014;Kourbeli et al, 2021;World Health Organization, 2021c).…”

“…In contrast to other trypanosomatids, the part of the life cycle of T. brucei in the mammalian host occurs completely in the extracellular space. During the lifecycle of Leishmania sp the parasite alternates between the infective promastigote stage generated in the intestine of the insect vector and the replicative amastigote form inside the host macrophages (Brindha et al, 2021;Kourbeli et al, 2021). Although these trypanosomatid protozoan parasites show important differences, they are transmitted by different insect vectors and are responsible for clinically different human diseases, it has been demonstrated that they show relevant similarities related to their biology.…”