Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase

Leah S. Torrie, David A. Robinson, Michael Thomas, Judith V Hobrath, Sharon M Shepherd, John M. Post, Eun-Jung Ko, Rafael Augusto Alves Ferreira, Claire J. MacKenzie, Karolina Wrobel, Darren Edwards, Ian H. Gilbert, David W Gray, Alan H. Fairlamb, Manu De Rycker.

ACS Infect. Dis. 2020,  just accepted.

Publication Date:April 10, 2020

Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in the 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 (‘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 non-competitive mode of inhibition. Homology modelling 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 provides a novel strategy in the search for new therapeutics for kinetoplastid diseases.