ArticlePLoS neglected tropical diseases2012
A static-cidal assay for Trypanosoma brucei to aid hit prioritisation for progression into drug discovery programmes.
Article in PLoS neglected tropical diseases, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues.Journal of medicinal chemistry · 2023Article
- Selenium Derivatives as Promising Therapy for Chagas Disease:ACS infectious diseases · 2021Article
- Library of Selenocyanate and Diselenide Derivatives as In Vivo Antichagasic Compounds TargetingPharmaceuticals (Basel, Switzerland) · 2021Article
- Investigation of pyrimidine nucleoside analogues as chemical probes to assess compound effects on the proliferation of Trypanosoma cruzi intracellular parasites.PLoS neglected tropical diseases · 2020Article
- Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis.Tropical medicine and infectious disease · 2020Article
- Insights into Chagas treatment based on the potential of bacteriocin AS-48.International journal for parasitology. Drugs and drug resistance · 2019Article
- Insights into antitrypanosomal drug mode-of-action from cytology-based profiling.PLoS neglected tropical diseases · 2018Article
- Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48.International journal for parasitology. Drugs and drug resistance · 2018Article
- Mitochondrial DNA is critical for longevity and metabolism of transmission stage Trypanosoma brucei.PLoS pathogens · 2018Article
- In vitro and in vivo pharmacodynamics of three novel antileishmanial lead series.International journal for parasitology. Drugs and drug resistance · 2018Article
- Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nature reviews. Microbiology · 2017Review
- Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis.Scientific reports · 2016Article
- Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade.PLoS neglected tropical diseases · 2016Article
- Discovery of Inhibitors of Trypanosoma brucei by Phenotypic Screening of a Focused Protein Kinase Library.ChemMedChem · 2015Article
- Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei.Journal of medicinal chemistry · 2015Article
- Development and Validation of a Novel Leishmania donovani Screening Cascade for High-Throughput Screening Using a Novel Axenic Assay with High Predictivity of Leishmanicidal Intracellular Activity.PLoS neglected tropical diseases · 2015Article
- Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign.PLoS neglected tropical diseases · 2014Article
- High-throughput chemical screening for antivirulence developmental phenotypes in Trypanosoma brucei.Eukaryotic cell · 2014Article
- Antiparasitic chemotherapy: from genomes to mechanisms.Annual review of pharmacology and toxicology · 2014Review
- Luminescent multiplex viability assay for Trypanosoma brucei gambiense.Parasites & vectors · 2013Article
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Authors and funding
6 authors.
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Abstract
Human African Trypanosomiasis is a vector-borne disease of sub-Saharan Africa that causes significant morbidity and mortality. Current therapies have many drawbacks, and there is an urgent need for new, better medicines. Ideally such new treatments should be fast-acting cidal agents that cure the disease in as few doses as possible. Screening assays used for hit-discovery campaigns often do not distinguish cytocidal from cytostatic compounds and further detailed follow-up experiments are required. Such studies usually do not have the throughput required to test the large numbers of hits produced in a primary high-throughput screen. Here, we present a 384-well assay that is compatible with high-throughput screening and provides an initial indication of the cidal nature of a compound. The assay produces growth curves at ten compound concentrations by assessing trypanosome counts at 4, 24 and 48 hours after compound addition. A reduction in trypanosome counts over time is used as a marker for cidal activity. The lowest concentration at which cell killing is seen is a quantitative measure for the cidal activity of the compound. We show that the assay can identify compounds that have trypanostatic activity rather than cidal activity, and importantly, that results from primary high-throughput assays can overestimate the potency of compounds significantly. This is due to biphasic growth inhibition, which remains hidden at low starting cell densities and is revealed in our static-cidal assay. The assay presented here provides an important tool to follow-up hits from high-throughput screening campaigns and avoid progression of compounds that have poor prospects due to lack of cidal activity or overestimated potency.
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