Optimization of a binding fragment targeting the “enlarged methionine pocket” leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors

Abstract

Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the “enlarged methionine pocket” (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4 nM.

Targeting tRNA-Synthetase Interactions towards Novel Therapeutic Discovery Against Eukaryotic Pathogens

“…While some aaRS inhibitors have successfully made it to the clinic, including the IleRS-targeting mupirocin [16], ProRS inhibitor halofuginone [17], and the LeuRS inhibitor tavaborole [18,19], there are likely many potential aaRS drugs still to be identified. Target-based approaches relying on structural data and sequence identity have previously been used to try and predict novel trypanosome aaRS drug targets [20-22] with some recent success [23]. While structure-based approaches have their utility, exploiting tRNA-aaRS interactions has been under-explored for its therapeutic potential.…”

Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens

“…While some aaRS inhibitors have successfully made it to the clinic, including the IleRS-targeting mupirocin [16], ProRS inhibitor halofuginone [17], and the LeuRS inhibitor tavaborole [18,19], there are likely many potential aaRS drugs still to be identified. Target-based approaches relying on structural data and sequence identity have previously been used to try and predict novel trypanosome aaRS drug targets [20][21][22] with some recent success [23]. While structure-based approaches have their utility, exploiting tRNA-aaRS interactions has been under-explored for its therapeutic potential.…”

Molecular basis for diaryldiamine selectivity and competition with tRNA in a type 2 methionyl-tRNA synthetase from a Gram-negative bacterium

“…Nevertheless, although many of these molecules were active against bacterial pathogens, they lacked selectivity, which restricted their use to biochemical and structural studies only (27). By contrast, an aminoquinolinonebased inhibitor of Staphylococcus aureus MetRS identified by high-throughput screening (28) served as inspiration for the development of potent derivatives with activities over a wide range of protozoans and Gram-positive pathogens (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).…”