ArticlePLoS neglected tropical diseases2015
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.
Article in PLoS neglected tropical diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Antileishmanial Activities of Methanol Extract and Solvent Fraction ofAdvances in pharmacological and pharmaceutical sciences · 2025Article
- Identification of a potent and selective LAPTc inhibitor by RapidFire-Mass Spectrometry, with antichagasic activity.PLoS neglected tropical diseases · 2024Article
- Past and future of trypanosomatids high-throughput phenotypic screening.Memorias do Instituto Oswaldo Cruz · 2022Article
- Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents.RSC 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
- Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Pharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovani.ACS infectious diseases · 2019Article
- Utilization of proliferable extracellular amastigotes for transient gene expression, drug sensitivity assay, and CRISPR/Cas9-mediated gene knockout in Trypanosoma cruzi.PLoS neglected tropical diseases · 2019Article
- High Throughput and Computational Repurposing for Neglected Diseases.Pharmaceutical research · 2018Review
- Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis.International journal for parasitology. Drugs and drug resistance · 2018Review
- Importance of secondary screening with clinical isolates for anti-leishmania drug discovery.Scientific reports · 2018Article
- Article
- Chemical probes and drug leads from advances in synthetic planning and methodology.Nature reviews. Drug discovery · 2018Review
- Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening.PLoS neglected tropical diseases · 2017Article
- Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani.ACS infectious diseases · 2017Article
- Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nature reviews. Microbiology · 2017Review
- Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs.Antimicrobial agents and chemotherapy · 2016Article
- Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade.PLoS neglected tropical diseases · 2016Article
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Authors and funding
8 authors.
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Abstract
Visceral leishmaniasis is an important parasitic disease of the developing world with a limited arsenal of drugs available for treatment. The existing drugs have significant deficiencies so there is an urgent need for new and improved drugs. In the human host, Leishmania are obligate intracellular parasites which poses particular challenges in terms of drug discovery. To achieve sufficient throughput and robustness, free-living parasites are often used in primary screening assays as a surrogate for the more complex intracellular assays. We and others have found that such axenic assays have a high false positive rate relative to the intracellular assays, and that this limits their usefulness as a primary platform for screening of large compound collections. While many different reasons could lie behind the poor translation from axenic parasite to intracellular parasite, we show here that a key factor is the identification of growth slowing and cytostatic compounds by axenic assays in addition to the more desirable cytocidal compounds. We present a screening cascade based on a novel cytocidal-only axenic amastigote assay, developed by increasing starting density of cells and lowering the limit of detection, and show that it has a much improved translation to the intracellular assay. We propose that this assay is an improved primary platform in a new Leishmania screening cascade designed for the screening of large compound collections. This cascade was employed to screen a diversity-oriented-synthesis library, and yielded two novel antileishmanial chemotypes. The approach we have taken may have broad relevance to anti-infective and anti-parasitic drug discovery.
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