ArticleScientific reports2019
Discovery of novel hit compounds with broad activity against visceral and cutaneous Leishmania species by comparative phenotypic screening.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- High-throughput screening identifies novel chemical scaffolds targeting Leishmania donovani parasites.World journal of microbiology & biotechnology · 2025Article
- Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years.Microorganisms · 2023Review
- Trifloxystrobin blocks the growth of Theileria parasites and is a promising drug to treat Buparvaquone resistance.Communications biology · 2022Article
- Cutaneous Leishmaniasis: A 2022 Updated Narrative Review into Diagnosis and Management Developments.American journal of clinical dermatology · 2022Review
- A Simple Bioluminescent Assay for the Screening of Cytotoxic Molecules Against the Intracellular Form of Leishmania infantum.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Pre-clinical evaluation of LASSBio-1491: From in vitro pharmacokinetic study to in vivo leishmanicidal activity.PloS one · 2022Article
- Paving the Way: Contributions of Big Data to Apicomplexan and Kinetoplastid Research.Frontiers in cellular and infection microbiology · 2022Review
- Past and future of trypanosomatids high-throughput phenotypic screening.Memorias do Instituto Oswaldo Cruz · 2022Article
- Bioprospecting marine actinomycetes for antileishmanial drugs: current perspectives and future prospects.Heliyon · 2021Review
- High Content Analysis of Macrophage-TargetingMicroorganisms · 2021Article
- Towards discovery of new leishmanicidal scaffolds able to inhibitJournal of enzyme inhibition and medicinal chemistry · 2020Article
- A Multi-Species Phenotypic Screening Assay for Leishmaniasis Drug Discovery Shows That Active Compounds Display a High Degree of Species-Specificity.Molecules (Basel, Switzerland) · 2020Article
- Infectivity and Drug Susceptibility Profiling of DifferentPathogens (Basel, Switzerland) · 2020Article
- Computational approaches for drug discovery against trypanosomatid-caused diseases.Parasitology · 2020Review
Corrections and comments
- Erratum issued
Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The limited success of recent phenotypic anti-leishmanial drug screening campaigns calls for new screening strategies for the discovery of clinically relevant hits. Here we present such a novel strategy based on physiologically relevant, ex vivo biology. We established high content phenotypic assays that combine primary murine macrophages and lesion-derived, virulent L. donovani and L. amazonensis amastigotes, which we applied to validate previously identified, anti-leishmanial hit compounds referred to as 'GSK Leish-Box'. Together with secondary screens using cultured promastigotes, our pipeline distinguished stage- and/or species-specific compounds, including 20 hits with broad activity at 10 µM against intracellular amastigotes of both viscerotropic and dermotropic Leishmania. Even though the GSK Leish-Box hits were identified by phenotypic screening using THP-1 macrophage-like cells hosting culture-derived L. donovani LdBob parasites, our ex vivo assays only validated anti-leishmanial activity at 10 µM on intra-macrophagic L. donovani for 23 out of the 188 GSK Leish-Box hits. In conclusion, our comparative approach allowed the identification of hits with broad anti-leishmanial activity that represent interesting novel candidates to be tested in animal models. Physiologically more relevant screening approaches such as described here may reduce the very high attrition rate observed during pre-clinical and clinical phases of the drug development process.
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