Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl‐tRNA synthetase 1

Abstract

Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.

Assessment of The Broad-Spectrum Host Targeting Antiviral Efficacy of Halofuginone Hydrobromide in Human Airway, Intestinal and Brain Organoid Models

“…The speed of peptide bond formation is significantly influenced by polyproline (PP or PPP) motifs, with abundant PP-motifs resulting in ribosome pauses that significantly slows protein translation. It has been previously stated that the efficacy of HH, a competitive inhibitor to the catalytic activity of PARS1, is specific to proline-rich proteins rather than proline rare proteins (Krafczyk et al, 2021;Yoon et al, 2023). However, the abundance of PP-motifs also plays a role and this is evident in the reduced biosynthesis of collagen I, a protein abundant in proline and PP-motifs, following HH treatment (Yoon et al, 2023), see Supplementary Table 3.…”

“…The molecular target of HH is Prolyl-tRNA synthetase 1 (PARS1) an aminoacyl-tRNA synthetase (ARSs), that facilitates the covalent ligation of proline to proline-tRNAs for protein synthesis (Hwang et al, 2019;Keller et al, 2012;Yoon et al, 2023). The four codons that code for proline is recognized by three distinct tRNAs, which are all charged by PARS1.…”

Cardiomyocyte-Specific Loss of Glutamyl-prolyl-tRNA Synthetase Leads to Disturbed Protein Homeostasis and Dilated Cardiomyopathy

“…Multiple prolyl-tRNA synthetase inhibitors are currently being evaluated for treating various human diseases spanning from infectious disease to cancer [ 7 , 8 , 9 ]. Halofuginone, a Chinese medicine-derived prolyl-tRNA synthetase-specific inhibitor, and a recently developed novel compound, DWN12088, have been used in pre-clinical and clinical trials for anti-fibrosis treatment [ 9 , 10 , 11 ].…”

“…Multiple prolyl-tRNA synthetase inhibitors are currently being evaluated for treating various human diseases spanning from infectious disease to cancer [ 7 , 8 , 9 ]. Halofuginone, a Chinese medicine-derived prolyl-tRNA synthetase-specific inhibitor, and a recently developed novel compound, DWN12088, have been used in pre-clinical and clinical trials for anti-fibrosis treatment [ 9 , 10 , 11 ]. Therefore, inhibiting prolyl-tRNA synthetase activity using its specific inhibitor or a reduction in EPRS1 expression represents a promising therapeutic strategy in treating fibrosis across multiple organs [ 3 , 7 , 10 ].…”

Cardiomyocyte-specific Loss of Glutamyl-prolyl-tRNA Synthetase Leads to Disturbed Protein Homeostasis and Dilated Cardiomyopathy

“…Multiple prolyl-tRNA synthetase inhibitors are currently being evaluated for treating various human diseases spanning from infectious disease to cancer [8][9][10] . Halofuginone, a Chinese medicine-derived prolyl-tRNA synthetase-specific inhibitor, and a recently developed novel compound, DWN12088, have been used in pre-clinical and clinical trials for anti-fibrosis treatment 10,11 .…”