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Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei

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Abstract

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.

Graphical abstract: Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei

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Supplementary files

Article information


Submitted
20 Feb 2020
Accepted
21 Apr 2020
First published
18 May 2020

RSC Med. Chem., 2020, Advance Article
Article type
Research Article

Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei

Z. Zhang, X. Barros-Álvarez, J. R. Gillespie, R. M. Ranade, W. Huang, S. Shibata, N. M. R. Molasky, O. Faghih, A. Mushtaq, R. K. M. Choy, E. de Hostos, W. G. J. Hol, C. L. M. J. Verlinde, F. S. Buckner and E. Fan, RSC Med. Chem., 2020, Advance Article , DOI: 10.1039/D0MD00057D

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