한빛사논문
- 조회383
Junhyeong Yim1, Jaeseok Lee2, Sihyeong Yi3, Ja Young Koo3, Sangmi Oh 3, Hankum Park 3,7, Seong Soon Kim4, Myung Ae Bae4,5, Jongmin Park2,6 and Seung Bum Park1,3
1Department of Biophysics and Chemical Biology, Seoul National University, Seoul 08826, Korea.
2Department of Chemistry, Kangwon National University, Chuncheon 24341, Korea.
3CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul 08826, Korea.
4Bio Platform Technology Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.
5Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34114, Korea.
6Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon 24341, Korea.
7Present address: Department of Dental Sciences, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Korea
Corresponding authors : Correspondence to Jongmin Park or Seung Bum Park.
Abstract
Neuroinflammation is one of the critical processes implicated in central nervous system (CNS) diseases. Therefore, alleviating neuroinflammation has been highlighted as a therapeutic strategy for treating CNS disorders. However, the complexity of neuroinflammatory processes and poor drug transport to the brain are considerable hurdles to the efficient control of neuroinflammation using small-molecule therapeutics. Thus, there is a significant demand for new chemical entities (NCEs) targeting neuroinflammation. Herein, we rediscovered benzopyran-embedded tubulin inhibitor 1 as an anti-neuroinflammatory agent via phenotype-based screening. A competitive photoaffinity labeling study revealed that compound 1 binds to tubulin at the colchicine-binding site. Structure–activity relationship analysis of 1’s analogs identified SB26019 as a lead compound with enhanced anti-neuroinflammatory efficacy. Mechanistic studies revealed that upregulation of the tubulin monomer was critical for the anti-neuroinflammatory activity of SB26019. We serendipitously found that the tubulin monomer recruits p65, inhibiting its translocation from the cytosol to the nucleus and blocking NF-κB-mediated inflammatory pathways. Further in vivo validation using a neuroinflammation mouse model demonstrated that SB26019 suppressed microglial activation by downregulating lba-1 and proinflammatory cytokines. Intraperitoneal administration of SB26019 showed its therapeutic potential as an NCE for successful anti-neuroinflammatory regulation. Along with the recent growing demands on tubulin modulators for treating various inflammatory diseases, our results suggest that colchicine-binding site-specific modulation of tubulins can be a potential strategy for preventing neuroinflammation and treating CNS diseases.
논문정보
- Research article
- 2022년 12월 (BRIC 등록일 2022-12-15)
- 국내 연구진
- 생명과학 > 분자생물학
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