Abstract
Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series). Crystallographic studies revealed that MetRS02 compounds bind to an allosteric pocket in L. major MetRS not previously described, and enzymatic studies demonstrated a noncompetitive mode of inhibition. Homology modeling of the Trypanosoma cruzi MetRS enzyme revealed key differences in the allosteric pocket between the T. cruzi and Leishmania enzymes. These provide a likely explanation for the lower MetRS02 potencies that we observed for the T. cruzi enzyme compared to the Leishmania enzyme. The identification of a new series of MetRS inhibitors and the discovery of a new binding site in kinetoplastid MetRS enzymes provide a novel strategy in the search for new therapeutics for kinetoplastid diseases.
Highlights
Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani
Due to the pivotal role that MetRS plays in protein synthesis, this enzyme has been described as a validated drug target in many disease-relevant organisms,[1−6] and several drug discovery programs against this target have been initiated.[1,2,4,7−14] In particular, MetRS has been successfully exploited as a target in Gram-positive bacteria with MetRS inhibitor CRS3123 having recently completed two phase I clinical trials for the treatment of Clostridium dif f icile infections.[13,15]
In addition to Gram-positive bacteria, MetRS has been validated as a drug target in kinetoplastid parasites.[5,6,16−18] Trypanosoma brucei subspecies, Leishmania species, and Trypanosoma cruzi are the causative agents of human African trypanosomiasis, leishmaniasis, and Chagas disease, respectively
Summary
Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites Trypanosoma brucei and Leishmania donovani. In addition to Gram-positive bacteria, MetRS has been validated as a drug target in kinetoplastid parasites.[5,6,16−18] Trypanosoma brucei subspecies, Leishmania species, and Trypanosoma cruzi are the causative agents of human African trypanosomiasis, leishmaniasis, and Chagas disease, respectively. These neglected tropical diseases affect millions of people,[19] and new treatment options are urgently required due to limitations of the currently available therapies: high cost, host toxicity, and emerging drug resistance.[20] identifying inhibitors of kinetoplastid MetRS provides a rational drug discovery strategy for these devastating diseases. Previous high-throughput screening and drug discovery efforts have successfully identified potent inhibitors of both T. brucei MetRS (TbMetRS) and L. donovani MetRS (LdMetRS),[5,6,16−18,21−23] with well-characterized binding sites and modes of inhibition defined.[6,16−18,21,22,24,25] Interestingly, there is little chemical diversity found in the kinetoplastid MetRS inhibitors identified to date, with hit compounds sharing the same aminoquinolone core scaffold (compound series MetRS01) and binding to two well-characterized sites of the enzyme (the methionine pocket and an adjacent, auxiliary pocket)[6,21,22,24,25] that are highly conserved across all kinetoplastid MetRS enzymes.[26]
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