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ID: ALA4402548
Journal: Eur J Med Chem
Title: Discovery of novel tRNA-amino acid dual-site inhibitors against threonyl-tRNA synthetase by fragment-based target hopping.
Authors: Guo J, Chen B, Yu Y, Cheng B, Cheng Y, Ju Y, Gu Q, Xu J, Zhou H.
Abstract: Threonyl-tRNA synthetase (ThrRS) is a key member of the aminoacyl-tRNA synthetase (aaRS) family that plays essential roles in protein biosynthesis, and ThrRS inhibitors have potential in the therapy of multiple diseases, such as microbial infections and cancers. Based on a unique tRNA-amino acid dual-site inhibitory mechanism identified recently with the herb-derived prolyl-tRNA synthetase (ProRS) inhibitor halofuginone (HF), a series of compounds have been designed and synthesized by employing a fragment-based target hopping approach to simultaneously target the tRNAThr and l-threonine binding pockets of ThrRS. Among them, compound 30d showed an IC50 value of 1.4 μM against Salmonella enterica ThrRS (SeThrRS) and MIC values of 16-32 μg/mL against the tested bacterial strains. The cocrystal structure of SeThrRS in complex with 30d was determined at high resolution, revealing that 30d simultaneously occupies both binding pockets for the nucleotide A76 of tRNAThr and l-threonine in an ATP-independent manner, a novel mechanism compared to all other reported ThrRS inhibitors. Our study provides a new class of ThrRS inhibitors, and more importantly, it presents the first experimental evidence that the tRNA-amino acid dual-site inhibitory mechanism could apply to other aaRSs beyond ProRS, thus providing great opportunities for designing new mechanistic inhibitors for aaRS-based therapeutics.
CiteXplore: 31821989