ArticleCell chemical biology2021
Multiple unbiased approaches identify oxidosqualene cyclase as the molecular target of a promising anti-leishmanial.
Article in Cell chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 25 citations in OpenAlex.
- Late-Stage Functionalization via Thianthrenation: A Reaction Enabling Rapid Preparation of Drug Beads for Chemical Pulldown.Journal of medicinal chemistry · 2026Article
- From fruit to function: Squalene synthase driven triterpenoids biosynthesis inFood chemistry: X · 2026Article
- Untargeted metabolomics for triaging of cytochrome b inhibitors during Chagas' disease drug discovery.PLoS neglected tropical diseases · 2026Article
- Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery.Journal of medicinal chemistry · 2025Article
- Antitrypanosomal quinazolines targeting lysyl-tRNA synthetase show partial efficacy in a mouse model of acute Chagas disease.Science translational medicine · 2025Article
- Article
- Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.PLoS pathogens · 2024Article
- Investigating Antiprotozoal Chemotherapies with Novel Proteomic Tools-Chances and Limitations: A Critical Review.International journal of molecular sciences · 2024Review
- Identification and Validation of Compounds TargetingACS infectious diseases · 2024Article
- The Potential Use of Peptides in the Fight against Chagas Disease and Leishmaniasis.Pharmaceutics · 2024Review
- The critical role of mode of action studies in kinetoplastid drug discovery.Frontiers in drug discovery · 2023Article
- Toolkit of Approaches To Support Target-Focused Drug Discovery forACS infectious diseases · 2022Article
- Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas' Disease.Antimicrobial agents and chemotherapy · 2022Article
- Utilizing thermal proteome profiling to identify the molecular targets of anti-leishmanial compounds.STAR protocols · 2021Article
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Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
Abstract
Phenotypic screening identified a benzothiophene compound with activity against Leishmania donovani, the causative agent of visceral leishmaniasis. Using multiple orthogonal approaches, oxidosqualene cyclase (OSC), a key enzyme of sterol biosynthesis, was identified as the target of this racemic compound and its enantiomers. Whole genome sequencing and screening of a genome-wide overexpression library confirmed that OSC gene amplification is associated with resistance to compound 1. Introduction of an ectopic copy of the OSC gene into wild-type cells reduced susceptibility to these compounds confirming the role of this enzyme in resistance. Biochemical analyses demonstrated the accumulation of the substrate of OSC and depletion of its product in compound (S)-1-treated-promastigotes and cell-free membrane preparations, respectively. Thermal proteome profiling confirmed that compound (S)-1 binds directly to OSC. Finally, modeling and docking studies identified key interactions between compound (S)-1 and the LdOSC active site. Strategies to improve the potency for this promising anti-leishmanial are proposed.
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Registered trials
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