한빛사논문
- 조회545
Jihoon Lee 1,2,3†, Ki Woon Sung 1,2,3†, Eun‑Jin Bae 2,4†, Dabin Yoon 3,5, Dasarang Kim 3, Jin Saem Lee 3, Da‑ha Park 2,4, Daniel Youngjae Park 1,2, Su Ran Mun 1,2, Soon Chul Kwon 1,2, Hye Yeon Kim 1,2, Joo‑Ok Min 2,4, Seung‑Jae Lee 2,4,6,7, Young Ho Suh 2,4* and Yong Tae Kwon 1,2,3,7,8*
1Cellular Degradation Biology Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea.
2Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea.
3AUTOTAC Bio Inc., Changkyunggung‑Ro 254, Jongno‑Gu, Seoul 03077, Republic of Korea.
4Neuroscience Research Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea.
5Department of Physical Education, Sejong University, Seoul 05006, Republic of Korea.
6Neuramedy Co. Ltd, Seoul 04796, Republic of Korea.
7Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea.
8Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea.
†Jihoon Lee, Ki Woon Sung and Eun-Jin Bae are authors equally contributed to this work.
*Corresponding author: correspondence to Young Ho Suh or Yong Tae Kwon
Abstract
Background: There are currently no disease-modifying therapeutics for Parkinson’s disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches to delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further disease progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a therapeutic modality to target α-syn. However, no PROTACs have yet shown to selectively degrade α-syn aggregates mainly owing to the limited capacity of the proteasome to degrade aggregates, necessitating the development of novel approaches to fundamentally eliminate α-syn aggregates.
Methods: We employed AUTOTAC (Autophagy-Targeting Chimera), a macroautophagy-based targeted protein degradation (TPD) platform developed in our earlier studies. A series of AUTOTAC chemicals was synthesized as chimeras that bind both α-syn aggregates and p62/SQSTM1/Sequestosome-1, an autophagic receptor. The efficacy of Autotacs was evaluated to target α-syn aggregates to phagophores and subsequently lysosomes for hydrolysis via p62-dependent macroautophagy. The target engagement was monitored by oligomerization and localization of p62 and autophagic markers. The therapeutic efficacy to rescue PD symptoms was characterized in cultured cells and mice. The PK/PD (pharmacokinetics/pharmacodynamics) profiles were investigated to develop an oral drug for PD.
Results: ATC161 induced selective degradation of α-syn aggregates at DC50 of ~ 100 nM. No apparent degradation was observed with monomeric α-syn. ATC161 mediated the targeting of α-syn aggregates to p62 by binding the ZZ domain and accelerating p62 self-polymerization. These p62-cargo complexes were delivered to autophagic membranes for lysosomal degradation. In PD cellular models, ATC161 exhibited therapeutic efficacy to reduce cell-to-cell transmission of α-syn and to rescue cells from the damages in DNA and mitochondria. In PD mice established by injecting α-syn preformed fibrils (PFFs) into brain striata via stereotaxic surgery, oral administration of ATC161 at 10 mg/kg induced the degradation of α-syn aggregates and reduced their propagation. ATC161 also mitigated the associated glial inflammatory response and improved muscle strength and locomotive activity.
Conclusion: AUTOTAC provides a platform to develop drugs for PD. ATC161, an oral drug with excellent PK/PD profiles, induces selective degradation of α-syn aggregates in vitro and in vivo. We suggest that ATC161 is a disease-modifying drug that degrades the pathogenic cause of PD.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-07-10)
- 국내 연구진
- 생명과학 > 분자생물학
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