Journal Article

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

Park, Joon Seok, Yoon, Ina, Kim, Sulhee, Cho, Minjae, Hwang, Kwang Yeon, Bang, Kyuhyeon, Cho, Seong Hyeok, Suh, Ji Hun, Oh, Sinae, Seo, Minjeong, Lee, Caroline, Lee, Bongyong, You, Kyung Ah, Kim, Jong Hyun, Park, Seonha, Kim, Sanga, Son, Jonghyeon, Bae, Da‐Jeong, Kim, Jong Min, Kim, Sunghoon, Park, Songhwa

2023

Overview

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. Synopsis Despite the therapeutic potential of PARS1 catalytic inhibition in fibrotic diseases, specific way to target this enzyme with safety is not provided. Here, DWN12088 is suggested as a novel PARS1 catalytic inhibitor with an asymmetric binding mode to PARS1 protomers to achieve safety for clinical use. DWN12088 shows the improved therapeutic index compared with halofuginone in in vitro and in vivo models of idiopathic pulmonary fibrosis. DWN12088 binds to PARS1 protomers with an asymmetric binding mode. Binding of the first DWN12088 to a PARS1 protomer interferes with binding of the second compound to the other protomer, conferring resistance to PARS1 inhibition at higher doses. Dose–response curve of DWN12088 shows a reduced hill slope due to its negative cooperativity in PARS1 binding, resulting in the increased therapeutic index of DWN12088. Graphical Abstract Despite the therapeutic potential of PARS1 catalytic inhibition in fibrotic diseases, specific way to target this enzyme with safety is not provided. Here, DWN12088 is suggested as a novel PARS1 catalytic inhibitor with an asymmetric binding mode to PARS1 protomers to achieve safety for clinical use.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Amino Acyl-tRNA Synthetases - chemistry / Amino Acyl-tRNA Synthetases - genetics / Amino Acyl-tRNA Synthetases - metabolism / Biosynthesis / Collagen / Disease / drug development / Drug dosages / EMBO08 / EMBO35 / FDA approval / Fibrosis / Humans / Lung diseases / Proline - genetics / Proline - metabolism / Proline-tRNA ligase / prolyl‐tRNA synthetase 1 / Protein Biosynthesis / Proteins / Pulmonary fibrosis / Safety / Transfer RNA / tRNA