ArticleAntimicrobial agents and chemotherapy2016
From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Characterization of the dual functions of Leishmania CK1.2 in both the parasite and the macrophage.PloS one · 2026Article
- Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans.Nature communications · 2025Article
- Structure-guided optimization of small molecules targeting the yeast casein kinase, Yck2, as a therapeutic strategy to combat Candida albicans.Research square · 2025Article
- Chemo-proteomics in antimalarial target identification and engagement.Medicinal research reviews · 2023Review
- 30th Annual GPPharmaceuticals (Basel, Switzerland) · 2023Article
- Current leishmaniasis drug discovery.RSC medicinal chemistry · 2022Review
- Effects of Structurally Different HDAC Inhibitors againstACS infectious diseases · 2022Article
- Review
- Identification of the Host Substratome ofFrontiers in cell and developmental biology · 2021Article
- Dangerous Duplicity: The Dual Functions of Casein Kinase 1 in Parasite Biology and Host Subversion.Frontiers in cellular and infection microbiology · 2021Review
- An Overview on the Therapeutics of Neglected Infectious Diseases-Leishmaniasis and Chagas Diseases.Frontiers in chemistry · 2021Review
- Review
- Need for sustainable approaches in antileishmanial drug discovery.Parasitology research · 2019Review
- Indirubin Analogues InhibitAntimicrobial agents and chemotherapy · 2019Article
- Discovery of novel hit compounds with broad activity against visceral and cutaneous Leishmania species by comparative phenotypic screening.Scientific reports · 2019Article
- Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis.International journal for parasitology. Drugs and drug resistance · 2018Review
- Review
- Emerging therapeutic targets for treatment of leishmaniasis.Expert opinion on therapeutic targets · 2018Review
- Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects.ACS infectious diseases · 2018Review
- Article
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Existing therapies for leishmaniases present significant limitations, such as toxic side effects, and are rendered inefficient by parasite resistance. It is of utmost importance to develop novel drugs targeting Leishmania that take these two limitations into consideration. We thus chose a target-based approach using an exoprotein kinase, Leishmania casein kinase 1.2 (LmCK1.2) that was recently shown to be essential for intracellular parasite survival and infectivity. We developed a four-step pipeline to identify novel selective antileishmanial compounds. In step 1, we screened 5,018 compounds from kinase-biased libraries with Leishmania and mammalian CK1 in order to identify hit compounds and assess their specificity. For step 2, we selected 88 compounds among those with the lowest 50% inhibitory concentration to test their biological activity on host-free parasites using a resazurin reduction assay and on intramacrophagic amastigotes using a high content phenotypic assay. Only 75 compounds showed antileishmanial activity and were retained for step 3 to evaluate their toxicity against mouse macrophages and human cell lines. The four compounds that displayed a selectivity index above 10 were then assessed for their affinity to LmCK1.2 using a target deconvolution strategy in step 4. Finally, we retained two compounds, PP2 and compound 42, for which LmCK1.2 seems to be the primary target. Using this four-step pipeline, we identify from several thousand molecules, two lead compounds with a selective antileishmanial activity.
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