Projects per year
Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust highthroughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable anti-leishmanial compound, MetRS remains an attractive anti-leishmanial drug target.
|Number of pages||10|
|Journal||ACS Infectious Diseases|
|Early online date||2 Oct 2017|
|Publication status||Published - Oct 2017|
- Drug Discovery
- tRNA synthetase
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- 3 Finished
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
A Translational Engine for Biomedical Discoveries (Strategic Grant)
1/01/13 → 30/09/15
Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)
Brenk, R., Fairlamb, A., Ferguson, M., Field, M., Gilbert, I., Gray, D., Hopkins, A., Horn, D., Read, K., Wyatt, P. & van Aalten, D.
1/02/11 → 1/07/17
- Drug Discovery Unit - Professor/Head of the Drug Discovery Unit & Roscoe Chair in Drug Discovery