Abstract
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 high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 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 antileishmanial compound, MetRS remains an attractive antileishmanial drug target.
Highlights
Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei
Targets are selected on the basis of those involved in highly essential biological pathways and extrapolation of validation data from related trypanosomatid parasites
Methionyl-tRNA synthetase (MetRS; EC 6.1.1.10) meets both criteria as this enzyme plays a crucial role in protein synthesis,[6] a fundamental pathway in all organisms, and has been validated as a druggable target in the closely related Trypanosoma brucei parasite, with inhibitors of T. brucei MetRS shown to cure T. brucei bloodstream infections in a mouse model of human African trypanosomiasis.[7−10] As a family, tRNA synthetases have been shown to be good targets in the anti-infectives space.[11−13] MetRS was prioritized as a target for entry into a Leishmania drug discovery program
Summary
Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 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 This compound failed to show efficacy in an animal model of leishmaniasis. Methionyl-tRNA synthetase (MetRS; EC 6.1.1.10) meets both criteria as this enzyme plays a crucial role in protein synthesis,[6] a fundamental pathway in all organisms, and has been validated as a druggable target in the closely related Trypanosoma brucei parasite, with inhibitors of T. brucei MetRS shown to cure T. brucei bloodstream infections in a mouse model of human African trypanosomiasis.[7−10] As a family, tRNA synthetases have been shown to be good targets in the anti-infectives space.[11−13] MetRS was prioritized as a target for entry into a Leishmania drug discovery program
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