scholarly journals Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach

2020 ◽  
Vol 5 (1) ◽  
pp. 23
Author(s):  
Buckner ◽  
Buchynskyy ◽  
Nagendar ◽  
Patrick ◽  
Gillespie ◽  
...  

The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis. Eleven scaffolds subsequently underwent hit-to-lead optimization using standard medicinal chemistry approaches. Over a period of six years in an academic setting, 1539 analogs to the 11 scaffolds were synthesized. Eight scaffolds were discontinued either due to insufficient improvement in antiparasitic activity (5), poor pharmacokinetic properties (2), or a slow (static) antiparasitic activity (1). Three scaffolds were optimized to the point of curing the acute and/or chronic T. brucei infection model in mice. The progress was accomplished without knowledge of the mechanism of action (MOA) for the compounds, although the MOA has been discovered in the interim for one compound series. Studies on the safety and toxicity of the compounds are planned to help select candidates for potential clinical development. This research demonstrates the power of the phenotypic drug discovery approach for neglected tropical diseases.

Author(s):  
Jan Hajek

This chapter on neglected tropical diseases (NTDs) provides an overview of the background and main contextual features of NTDs, and includes clear guidance on their clinical recognition and management. Recognizing the prevalence of NTDs in humanitarian settings, with their disproportional effect on the poor, this chapter covers the fundamentals of management of NTDs, and is especially helpful for the provider who may have little prior clinical experience with such conditions. It also includes detailed guidance on recognition and diagnosis of the main NTDs, such as dengue, human African trypanosomiasis, leishmaniasis, leprosy, and schistosomiasis, in settings with very limited diagnostic testing available.


2019 ◽  
Vol 24 (3) ◽  
pp. 346-361 ◽  
Author(s):  
Carolina B. Moraes ◽  
Gesa Witt ◽  
Maria Kuzikov ◽  
Bernhard Ellinger ◽  
Theodora Calogeropoulou ◽  
...  

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion–toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 ( TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.


2014 ◽  
Vol 58 (10) ◽  
pp. 5747-5757 ◽  
Author(s):  
Federica Giordani ◽  
Annamaria Buschini ◽  
Alessandro Baliani ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
...  

ABSTRACTThis paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity againstTrypanosoma bruceiinin vitroassays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse modelT. brucei rhodesienseSTIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential.


2014 ◽  
Vol 114 (22) ◽  
pp. 11138-11163 ◽  
Author(s):  
Mathew Njoroge ◽  
Nicholas M. Njuguna ◽  
Peggoty Mutai ◽  
Dennis S. B. Ongarora ◽  
Paul W. Smith ◽  
...  

2013 ◽  
Vol 5 (15) ◽  
pp. 1801-1841 ◽  
Author(s):  
Lori Ferrins ◽  
Raphaël Rahmani ◽  
Jonathan B Baell

2014 ◽  
Vol 20 (1) ◽  
pp. 70-81 ◽  
Author(s):  
Joana Faria ◽  
Carolina B. Moraes ◽  
Rita Song ◽  
Bruno S. Pascoalino ◽  
Nakyung Lee ◽  
...  

Human African trypanosomiasis (HAT) is a vector-transmitted tropical disease caused by the protozoan parasite Trypanosoma brucei. High-throughput screening (HTS) of small-molecule libraries in whole-cell assays is one of the most frequently used approaches in drug discovery for infectious diseases. To aid in drug discovery efforts for HAT, the SYBR Green assay was developed for T. brucei in a 384-well format. This semi-automated assay is cost- and time-effective, robust, and reproducible. The SYBR Green assay was compared to the resazurin assay by screening a library of 4000 putative kinase inhibitors, revealing a superior performance in terms of assay time, sensitivity, simplicity, and reproducibility, and resulting in a higher hit confirmation rate. Although the resazurin assay allows for comparatively improved detection of slow-killing compounds, it also has higher false-positive rates that are likely to arise from the assay experimental conditions. The compounds with the most potent antitrypanosomal activity were selected in both screens and grouped into 13 structural clusters, with 11 new scaffolds as antitrypanosomal agents. Several of the identified compounds had IC50 <1 µM coupled with high selectivity toward the parasite. The core structures of the scaffolds are shown, providing promising new starting points for drug discovery for HAT.


2010 ◽  
Vol 9 (1) ◽  
pp. 57 ◽  
Author(s):  
Pere P Simarro ◽  
Giuliano Cecchi ◽  
Massimo Paone ◽  
José R Franco ◽  
Abdoulaye Diarra ◽  
...  

Author(s):  
Christopher N Davis ◽  
Kat S Rock ◽  
Marina Antillon ◽  
Erick Mwamba Miaka ◽  
Matt J Keeling

Gambiense human African trypanosomiasis (gHAT) has been brought under control recently with village-based active screening playing a major role in case reduction. In the eve of elimination, we investigate how to optimise active screening in villages in the Democratic Republic of Congo, such that the expenses of screening programmes can be efficiently allocated while continuing to avert morbidity and mortality. We implement a cost-effectiveness analysis using a stochastic gHAT infection model for a range of active screening strategies and we calculate the net monetary benefit (NMB) of each strategy. High-coverage active screening strategies, occurring approximately annually, attain the highest NMB. We find that, for strategies stopping after one to three years of zero case reporting, the expected cost-benefits are very similar and we highlight the current recommended strategy (three years before stopping) is likely cost-effective, in addition to providing valuable information on whether transmission has been interrupted.


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