한빛사논문
- 조회731
Seung Hwan Son,1# Na-Rae Lee,2# Min Sung Gee,1# Chae Won Song2, Soo Jin Lee1, Sang-Kyung Lee3, Yoonji Lee4, Hee Jin Kim2, Jong Kil Lee,1,2* Kyung-Soo Inn,1,2* and Nam-Jung Kim1,2*
1College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
2Prazer Therapeutics Inc., Seoul 05836, Republic of Korea
3Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul 04763, Republic of Korea
4College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
#S.H.S., N.-R.L., and M.S.G. contributed equally.
Corresponding Authors: Jong Kil Lee , Kyung-Soo Inn, Nam-Jung Kim
Abstract
Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs). Herein, we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner. Given that the activation of p38 MAPK plays pivotal roles in the pathophysiology of Alzheimer’s disease (AD), selective degradation of p-p38 may provide an attractive therapeutic option for the treatment of AD. In the 5xFAD transgenic mice model of AD, intranasal treatment of PRZ-18002 reduces p-p38 levels and alleviates microglia activation and amyloid beta (Aβ) deposition, leading to subsequent improvement of spatial learning and memory. Collectively, our findings suggest that PRZ-18002 ameliorates AD pathophysiology via selective degradation of p-p38, highlighting a novel therapeutic TPD modality that targets a specific PTM to induce selective degradation of neurodegenerative disease-associated protein.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-08)
- 국내 연구진
- 의약학 > 약학
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