윤다빈 (오토텍바이오, 세종대학교)

한빛사논문

조회407

윤다빈Dabin Yoon

오토텍바이오, 세종대학교

Autophagy, Nov 01 2023, | https://doi.org/10.1080/15548627.2023.2274711 Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform

Jihoon Lee^1,2,3#, Dabin Yoon ^{3,4^#}, Ki Woon Sung^{1,2,3^#}, Eun-Jin Bae ^2,5, Da-Ha Park ^2,5, Young Ho Suh^2,5, Yong Tae Kwon ^1,2,3,6,7

¹Cellular Degradation Biology Center, College of Medicine, Seoul National University, Seoul, Republic of Korea.

²Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.

³AUTOTAC Bio Inc, Seoul, Republic of Korea.

⁴Department of Physical Education, Sejong University, Seoul, Republic of Korea.

⁵Neuroscience Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea.

⁶Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea.

⁷Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Republic of Korea.

^#Contributed equally

Correspondence : Young Ho Suh, Yong Tae Kwon

Abstract

Parkinson disease (PD) characterized by dopaminergic neuronal loss is caused by aggregation of misfolded SNCA/α-synuclein. We recently developed autophagy-targeting chimera (AUTOTAC), a targeted protein degradation (TPD) technology based on the macroautophagy/autophagy-lysosome pathway (ALP). In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates. The autophagy-targeting ligand (ATL) of ATC161 was designed to allosterically activate the autophagy receptor SQSTSM1/p62 (sequestosome 1), a key step for targeting SNCA aggregates to the phagophore. The lysosomal degradation of SNCA aggregates by ATC161 acutely occurs at DC50 of 100-500 nM with no significant off-target degradation of monomeric SNCA. ATC161 protects cells from DNA and mitochondrial damage by SNCA aggregates. In PD model mice, oral administration of ATC161 decreases the level of SNCA aggregates and their propagation across brain regions, which mitigates glial inflammatory responses and improves muscle strength and locomotive activity. An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-11-03)
연구진국내 연구진
분야 생명과학 > 분자생물학

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