The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets

Abstract

Human trypanosomiasis and leishmaniasis are vector‐borne neglected tropical diseases caused by infection with the protozoan parasites Trypanosoma spp. and Leishmania spp., respectively. Once restricted to endemic areas, these diseases are now distributed worldwide due to human migration, climate change, and anthropogenic disturbance, causing significant health and economic burden globally. The current chemotherapy used to treat these diseases has limited efficacy, and drug resistance is spreading. Hence, new drugs are urgently needed. Phenotypic compound screenings have prevailed as the leading method to discover new drug candidates against these diseases. However, the publication of the complete genome sequences of multiple strains, advances in the application of CRISPR/Cas9 technology, and in vivo bioluminescence‐based imaging have set the stage for advancing target‐based drug discovery. This review analyses the limitations of the narrow pool of available drugs presently used for treating these diseases. It describes the current drug‐based clinical trials highlighting the most promising leads. Furthermore, the review presents a focused discussion on the most important biological and pharmacological challenges that target‐based drug discovery programs must overcome to advance drug candidates. Finally, it examines the advantages and limitations of modern research tools designed to identify and validate essential genes as drug targets, including genomic editing applications and in vivo imaging.

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

“…These drugs are inhibiting enzymes of the glycolytic pathway and fatty acid oxidation in Leishmania parasites. [ 44 ] While pentavalent antimonials are used as first-line drugs, their efficacy varies significantly depending on the country, and especially in India, where high rates of resistance are observed [ 45 ].…”

Effects of Propolis on Infectious Diseases of Medical Relevance

“…For more than six decades, pentavalent antimonials (SbV) were the first-line drugs against leishmaniasis; however, the toxicity and resistance of the parasites are the main limitation of these drugs [ 137 ]. Other treatments such as pentamidine, paromomycin, or amphotericin B has been employed, but its high costs and side effects make it difficult to use [ 137 , 138 ]. Therefore, alternatives are urgently required that complement and help with the adequate treatment of leishmaniasis.…”

Epitranscriptome machinery in Trypanosomatids: New players on the table?

“…Most of the known species are parasites belonging to the Trypanosoma and Leishmania genera that have a huge public health and economic impact. The diseases that these parasites cause are considered some of the most important neglected tropical diseases, affecting nearly 22 million people globally (Altamura et al., 2020; Buscher et al., 2017; Filardy et al., 2018; Okwor & Uzonna, 2016; Perez‐Molina & Molina, 2018).…”