Structural insights into the inhibition of M. tuberculosis Prolyl-tRNA synthetase by derivatives of 3-aminopyrazine-2-carboxamide

TL;DR

This study reveals how 3-aminopyrazine-2-carboxamide derivatives inhibit a key enzyme in tuberculosis bacteria, offering insights for developing selective anti-TB drugs.

Contribution

The paper provides structural evidence of selective inhibition of MtbProRS by 3-aminopyrazine-2-carboxamide derivatives over human ProRS.

Findings

Crystal structures show the inhibitors compete with ATP at the MtbProRS binding site.

A hydrogen bond between Glu144 and the inhibitor's amino group explains selective inhibition.

The compounds show antimycobacterial activity against drug-resistant TB strains.

Abstract

Tuberculosis (TB) is recognized as the second leading cause of death globally from a single infectious agent, following SARS-CoV-2 pneumonia. Aminoacyl-tRNA synthetases (aaRS) are essential enzymes responsible for attaching amino acids to their cognate tRNAs. These enzymes represent a promising set of targets for selective drug design due to the divergence between prokaryotic and eukaryotic aaRS. Recently, a new class of 3-aminopyrazine- 2-carboxamide derivatives has been identified as potent inhibitors of prolyl-tRNA synthetase (ProRS) from Mycobacterium tuberculosis (Mtb). These compounds exhibit significant antimycobacterial activity against Multi Drug Resistant strains of Mtb and demonstrate cytotoxicity against HepG2 human hepatocellular carcinoma cells. In this study, we present the crystal structures of MtbProRS in complex with five distinct 3-aminopyrazine-2-carboxamide derivatives. Structural analysis reveals that these inhibitors compete with ATP for the binding site of MtbProRS. Importantly, a critical hydrogen bond between the Glu144 of MtbProRS and the amino group of the carboxamide is identified, providing insights into the selective inhibition of MtbProRS over human ProRS.