State-of-the-Art in the Drug Discovery Pathway for Chagas Disease: A Framework for Drug Development and Target Validation

Abstract

Chagas disease is the most important protozoan infection in the Americas, and constitutes a significant public health concern throughout the world. Development of new medications against its etiologic agent, Trypanosoma cruzi , has been traditionally slow and difficult, lagging in comparison with diseases caused by other kinetoplastid parasites. Among the factors that explain this are the incompletely understood mechanisms of pathogenesis of T. cruzi infection and its complex set of interactions with the host in the chronic stage of the disease. These demand the performance of a variety of in vitro and in vivo assays as part of any drug development effort. In this review, we discuss recent breakthroughs in the understanding of the parasite’s life cycle and their implications in the search for new chemotherapeutics. For this, we present a framework to guide drug discovery efforts against Chagas disease, considering state-of-the-art preclinical models and recently developed tools for the identification and validation of molecular targets.

High-Throughput Phenotypic Screening and Machine Learning Methods Enabled the Selection of Broad-Spectrum Low-Toxicity Antitrypanosomatidic Agents

“…13 C NMR (101 MHz, MeOD): δ 152. 34, 140.83, 137.97, 125.13, 124.94, 123.15, 117.78 Synthesis of 6,2,4]thiadiazin-3(4H)-one 1,1-Dioxide (2). A solution of 3,4-dichloro-Nmethylaniline (8.0 g, 50 mmol, 1 equiv) in nitromethane (25 mL) was added to a stirred, ice cooled solution of chlorosulfonyl isocyanate (8.5 g, 60 mmol, 1,2 equiv) in nitromethane (25 mL) during 5 min, and the reaction was further stirred for 25 min.…”

“…Calcd for C 11 H 13 ClN 2 O 3 S: C, 45.76;H,4.54;N,9.70. Found: C,45.60;H,4.87;N,9.67 [1,2,4]thiadiazine 1,1-Dioxide (6). A solution of aniline (930 mg, 10 mmol, 1 equiv) in anhydrous DCM (40 mL) was added to a solution of N′-(chlorosulfonyl)-N,N-dimethylcarbamimidoyl chloride (2.1 g, 10 mmol, freshly prepared, 1 equiv) in anhydrous DCM (50 mL), and the mixture was stirred at r.t. for 30 min.…”

“…Infections caused by Trypanosomatidae such as Chagas diseases, Human African Trypanosomiasis (HAT), and Leishmaniasis account for 17% of the estimated global burden of all infectious diseases (700,000 deaths/year) . Chagas disease is caused by Trypanosoma cruzi ( Tc ) that is more diffused in South America; in its chronic form Chagas disease leads to severe organ damage, affecting mainly cardiovascular and digestive systems . HAT is mostly diffused in African countries and is caused by Trypanosoma brucei ( Tb ) subspecies; while Tb rhodesiense is responsible for a more acute infection and a faster-progressing disease that also affects the central nervous system, Tb gambiense establishes a chronic infection and a slow progression disease .…”

“…5 Chagas disease is caused by Trypanosoma cruzi ( Tc ) that is more diffused in South America; in its chronic form Chagas disease leads to severe organ damage, affecting mainly cardiovascular and digestive systems. 6 HAT is mostly diffused in African countries and is caused by Trypanosoma brucei ( Tb ) subspecies; while Tb rhodesiense is responsible for a more acute infection and a faster-progressing disease that also affects the central nervous system, Tb gambiense establishes a chronic infection and a slow progression disease. 7 Leishmaniasis is endemic in many tropical and subtropical countries and is caused by the infection of diverse Leishmania spp.…”

Development of bioluminescent reporter Trypanosoma cruzi and bioassay for compound screening

“…Despite the World Health Organization has raised attention towards CD by including it in the list of neglected tropical diseases (NTD), private investment in drug discovery remains scarce, leading to a notable lack of chemotherapeutic options (Weng et al, 2018). Several academic groups and, in the last decade, public-private partnership initiatives (i.e., DNDi) have contributed to nominating novel molecular targets or compounds as drug candidates against CD (Bhattacharya et al, 2020;Gabaldón-Figueira et al, 2023). It is well known that the drug discovery process is a long path with multiple bottlenecks that, at the hit discovery stage, include: assay development (for compound screening) and hit-to-lead optimization.…”