Projects per year
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.
|Number of pages||20|
|Journal||Cell Chemical Biology|
|Early online date||9 Mar 2021|
|Publication status||Published - 20 May 2021|
- oxidosqualene cyclase
- Leishmania donovani
- drug target
- mechanism of action
- neglected tropical diseases
- visceral leishmaniasis
- drug discovery
- neglected tropical disease
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
FingerprintDive into the research topics of 'Multiple unbiased approaches identify oxidosqualene cyclase as the molecular target of a promising anti-leishmanial'. Together they form a unique fingerprint.
Wellcome Centre for Anti-Infectives Research
Cook, S., De Rycker, M., Fairlamb, A., Ferguson, M., Field, M., Gilbert, I., Gray, D., Horn, D., Pawlowic, M., Read, K., Wyatt, P. & Wyllie, S.
1/04/17 → 31/03/24
Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)
Fairlamb, A., Field, M., Gilbert, I., Gray, D., Horn, D. & Wyatt, P.
1/01/15 → 31/12/20