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

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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere16940
JournalEMBO Molecular Medicine
Volume15
Issue number7
DOIs
Publication statusPublished - 2023 Jul 10

Bibliographical note

Funding Information:
This work was supported by the following grants: National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT (MSIT)) (2021R1A3B1076605) (Sunghoon Kim). NRF grant funded by Korean government (MSIT) (2020R1A2C2005670) (K.Y.H.). NRF grant funded by Korean government (MSIT) (2021R1C1C1013332) (I.Y.). Yonsei University Research Fund (2020‐22‐0358, 2020‐22‐0356 and 2021‐22‐0061) (Sunghoon Kim). Korea Drug Development Fund (KDDF) grant funded by Korean government (MSIT, Ministry of Trade, Industry, and Energy (MOTIE), and Ministry of Health and Welfare (MOHW)) (KDDF‐201812‐20) (J.S.P.).

Funding Information:
This work was supported by the following grants: National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT (MSIT)) (2021R1A3B1076605) (Sunghoon Kim). NRF grant funded by Korean government (MSIT) (2020R1A2C2005670) (K.Y.H.). NRF grant funded by Korean government (MSIT) (2021R1C1C1013332) (I.Y.). Yonsei University Research Fund (2020-22-0358, 2020-22-0356 and 2021-22-0061) (Sunghoon Kim). Korea Drug Development Fund (KDDF) grant funded by Korean government (MSIT, Ministry of Trade, Industry, and Energy (MOTIE), and Ministry of Health and Welfare (MOHW)) (KDDF-201812-20) (J.S.P.).

Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

  • collagen
  • drug development
  • fibrosis
  • prolyl-tRNA synthetase 1

ASJC Scopus subject areas

  • Molecular Medicine

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