Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei
- RSC Med Chem. 2020 May 18;11(8):885-895. doi: 10.1039/d0md00057d.
- 1. Department of Biochemistry , University of Washington , Seattle , WA 98195 , USA . Email: [email protected].
- 2. Department of Medicine , Division of Allergy & Infectious Disease , Center for Emerging & Re-emerging Infectious Disease (CERID) , University of Washington , Seattle , WA 98109 , USA . Email: [email protected].
- 3. PATH , San Francisco , CA 94108 , USA.
Based on crystal structures of Trypanosoma brucei methionyl-tRNA synthetase (TbMetRS) bound to inhibitors, we designed, synthesized, and evaluated two series of novel TbMetRS inhibitors targeting this Parasite enzyme. One series has a 1,3-dihydro-imidazol-2-one containing linker, the other has a rigid fused aromatic ring in the linker. For both series of compounds, potent inhibition of Parasite growth was achieved with EC50 < 10 nM and most compounds exhibited low general toxicity to mammalian cells with CC50s > 20 000 nM. Selectivity over human mitochondrial methionyl tRNA synthetase was also evaluated, using a cell-based mitochondrial protein synthesis assay, and selectivity in a range of 20-200-fold was achieved. The inhibitors exhibited poor permeability across the blood brain barrier, necessitating future efforts to optimize the compounds for use in late stage human African trypanosomiasis.