HARS2 Inhibitors

HARS2 inhibitors include a range of chemical compounds that exert their inhibitory effects through various biochemical mechanisms, affecting the functional activity of HARS2. One class of these compounds acts by compromising the process of tRNA charging, through competitive inhibition within the aminoacyl-tRNA synthetase family, ultimately reducing the efficiency of histidine attachment to tRNA, which is the primary function of HARS2. Others achieve inhibition by binding to the eukaryotic ribosomal subunit, specifically targeting the translocation or elongation steps in protein synthesis, leading to an indirect decrease in the amount of HARS2 synthesized, as the overall protein synthesis is hampered. Furthermore, some compounds chelate essential metal ions, which could compromise any metal-dependent enzymatic activity of HARS2, while others create a scarcity of cellular ATP, a necessary cofactor for the ligation action performed by HARS2, thusindirectly limiting its activity.

Additional mechanisms by which these inhibitors function include the interference with various stages of the protein synthesis machinery. Certain inhibitors mimic aminoacyl-tRNA, leading to premature termination of the growing polypeptide chain, which subsequently lowers the production of HARS2. There are also inhibitors that target the ribosomal subunit, preventing the peptidyl transferase reaction, or that freeze the ribosome's progress, thereby stalling the synthesis processes that are crucial for HARS2 production. Some function by disrupting mitochondrial protein synthesis, which could indirectly affect the mitochondrial form of HARS2. Moreover, there are inhibitors that act on the transcriptional level, inhibiting RNA polymerase II and subsequently decreasing the mRNA available for HARS2 synthesis.