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EMBO Mol. Med., 22 May 2023 | https://doi.org/10.15252/emmm.202216940 Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1

Ina Yoon ^1,2,†, Sulhee Kim ^3,†, Minjae Cho ⁴, Kyung Ah You ¹, Jonghyeon Son ³, Caroline Lee ⁴, Ji Hun Suh ^1,2, Da-Jeong Bae ⁴, Jong Min Kim ⁴, Sinae Oh ¹, Songhwa Park ¹, Sanga Kim ¹, Seong Hyeok Cho ¹, Seonha Park ³, Kyuhyeon Bang ³, Minjeong Seo ³, Jong Hyun Kim ^1,5, Bongyong Lee ^4,7, Joon Seok Park ⁴, Kwang Yeon Hwang ^*,3 and Sunghoon Kim^*,1,2,6

¹Institute for Artificial Intelligence and Biomedical Research, Medicinal Bioconvergence Research Center, Yonsei University, Incheon, Korea
²Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Korea
³Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
⁴Drug Discovery Center, Daewoong Pharmaceutical Co., Ltd, Yongin, Korea
⁵Department of Biochemistry, School of Medicine, Catholic University of Daegu, Daegu, Korea
⁶College of Medicine, Gangnam Severance Hospital, Yonsei University, Seoul, Korea
⁷Present address: Nextgen Bioscience, Seongnam, Korea

†These authors contributed equally to this work
*Corresponding author: correspondence to Kwang Yeon Hwang or Sunghoon Kim

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.

논문정보

형식Research article
게재일2023년 05월 (BRIC 등록일 2023-05-26)
연구진국내 연구진
분야 의약학 > 약학

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