Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of
            <i>Trypanosoma cruzi</i>
            , the Agent of Chagas' Disease

Engel, Juan C.; Ang, Kenny Kean‐Hooi; Chen, Steven; Arkin, Michelle R.; McKerrow, James H.; Doyle, Patricia S.

doi:10.1128/aac.01777-09

Cited by 102 publications

(126 citation statements)

References 59 publications

(69 reference statements)

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“…For some protozoan parasites, such as Trypanosoma brucei, which causes African sleeping sickness, high-throughput screening (HTS) has been possible 19,20 without the need for high-content imaging. However, for other protozoa such as Trypanosoma cruzi (Chagas disease) 21,22 and Leishmania species, 23,24 HCS offers the opportunity to improve and build on previous screens through its ability to test compounds against more clinically relevant stages of the life cycle.…”

Section: Drug Discovery For Ntdsmentioning

confidence: 99%

Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases: The A·WOL Experience

2014

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Neglected tropical diseases (NTDs) are a group of 17 diseases that typically affect poor people in tropical countries. Each has been neglected for decades in terms of funding, research, and policy, but the recent grouping of them into one unit, which can be targeted using integrated control measures, together with increased advocacy has helped to place them on the global health agenda. The World Health Organization has set ambitious goals to control or eliminate 10 NTDs by 2020 and launched a roadmap in January 2012 to guide this global plan. The result of the launch meeting, which brought together representatives from the pharmaceutical industry, donors, and politicians, was the London Declaration: a series of commitments to provide more drugs, research, and funds to achieve the 2020 goals. Drug discovery and development for these diseases are extremely challenging, and this article highlights these challenges in the context of the London Declaration, before focusing on an example of a drug discovery and development program for the NTDs onchocerciasis and lymphatic filariasis (the anti- Wolbachia consortium, A·WOL).

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Section: Drug Discovery For Ntdsmentioning

confidence: 99%

Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases: The A·WOL Experience

2014

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“…With critics of genetically modified parasites/host cells and the further development of technology an improved assay was developed that used whole unmodified cells and parasites. This assay was validated with a small library of FDA-approved drugs 51 . The development of analysis software further automates the campaigns and allows the additional mining of important data, for example, the toxicity for host cells 52 .…”

Section: Unfortunately and Unlike The Related Species Trypanosoma Brumentioning

confidence: 99%

Current and Future Chemotherapy for Chagas Disease

Gaspar¹,

Moraes²,

Freitas‐Junior³

et al. 2015

CMC

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American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease -a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates, posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments.In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. 2We will also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near future.

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“…The percentage of parasite inhibition with regard to controls was calculated as 100 Ϫ [(parasite counts in treated cells/parasite counts in untreated cells) ϫ 100]. The range of the assay window was calculated as mean values of the no-drug control wells/mean values of the drug (amphotericin B)-treated wells (25). The quality of each plate was determined by calculating the Z prime (Z=) factor (26) using the positive and negative controls on each plate.…”

Section: Animals and Parasitesmentioning

confidence: 99%

“…The RLUs of the signals were transformed to percentages of parasite inhibition (described previously). Hits were defined as compounds displaying Ͼ50% inhibition of light emission (15,17,25). The percentage of parasite inhibition with regard to controls was calculated as 100 Ϫ [(parasite counts in treated cells/parasite counts in untreated cells) ϫ 100].…”

Section: Animals and Parasitesmentioning

confidence: 99%

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

Peniche

Osorio

Renslo

et al. 2014

Antimicrob Agents Chemother

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e Leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (ELEC) derived from the draining lymph nodes of Leishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infected in vitro with L. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active against L. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC 50 ). We found 24 compounds (7%) that had an in vitro therapeutic index (IVTI; 50% cytotoxic/effective concentration [CC 50 ]/EC 50 ) > 100; 19 of the compounds had an EC 50 below 1 M. According to PubChem searchs, 17 of those compounds had not previously been reported to be active against Leishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis.

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Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

Cited by 102 publications

References 59 publications

Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases: The A·WOL Experience

Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases: The A·WOL Experience

Current and Future Chemotherapy for Chagas Disease

Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

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