PMID- 38481699
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240315
IS  - 2575-9108 (Electronic)
IS  - 2575-9108 (Linking)
VI  - 7
IP  - 3
DP  - 2024 Mar 8
TI  - Structure-Based Identification of Kelch-like ECH-Associated Protein 1 as a 
      Pharmacological Target of Electrophile-Containing Catechol-O-Methyltransferase 
      Inhibitors.
PG  - 693-706
LID - 10.1021/acsptsci.3c00281 [doi]
AB  - Entacapone and nitecapone are electrophile-containing 
      catechol-O-methyltransferase (COMT) inhibitors that are used to treat Parkinson's 
      disease in combination with L-DOPA. It is desirable to investigate whether they 
      can covalently bind to cellular protein targets using their reactive 
      electrophilic warheads. We identified Kelch-like ECH-associated protein 1 
      (KEAP1), a sensor for oxidative and electrophilic stress, as a potential 
      pharmacological target of both drugs by performing covalent-based reverse 
      docking. We confirmed that both drugs activate nuclear factor erythroid 2-related 
      factor 2 (NRF2) by reversibly modifying C151 on KEAP1. Both drugs can enhance the 
      expression of growth differentiation factor 15 (GDF15) and NRF2 downstream 
      antioxidant response element (ARE) genes, both in vitro and in vivo. Furthermore, 
      both drugs exhibit anti-inflammatory effects in an NRF2-dependent acute gout 
      model. Our findings suggest that these two drugs could be repurposed for the 
      treatment of NRF2-modulated inflammatory diseases, and the 
      3-methylene-acetylacetone group of nitecapone could serve as a new reversible 
      covalent warhead.
CI  - (c) 2024 American Chemical Society.
FAU - Wang, Ping
AU  - Wang P
AUID- ORCID: 0000-0001-7431-6575
AD  - College of Life Sciences, Beijing Normal University, No. 19 Xinjiekouwai Street, 
      Beijing 100875, China.
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Li, Yang
AU  - Li Y
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Yang, Jinyi
AU  - Yang J
AD  - Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 
      102206, China.
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Li, Ziwen
AU  - Li Z
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Ren, Xintong
AU  - Ren X
AD  - College of Life Sciences, Beijing Normal University, No. 19 Xinjiekouwai Street, 
      Beijing 100875, China.
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Meng, Qingshi
AU  - Meng Q
AD  - State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal 
      Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
FAU - Li, Pengfei
AU  - Li P
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Qin, Luzhe
AU  - Qin L
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
AD  - School of Life Sciences, Tsinghua University, Beijing 100084, China.
FAU - Li, Wei
AU  - Li W
AD  - RPXDs (Suzhou) Co., Ltd., Suzhou 215028, China.
FAU - Xie, Yuting
AU  - Xie Y
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Hou, Nannan
AU  - Hou N
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
FAU - Huang, Niu
AU  - Huang N
AUID- ORCID: 0000-0002-6912-033X
AD  - National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun 
      Life Science Park, Beijing 102206, China.
AD  - Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, 
      Beijing 102206, China.
LA  - eng
PT  - Journal Article
DEP - 20240213
PL  - United States
TA  - ACS Pharmacol Transl Sci
JT  - ACS pharmacology & translational science
JID - 101721411
PMC - PMC10928886
COIS- The authors declare no competing financial interest.
EDAT- 2024/03/14 06:46
MHDA- 2024/03/14 06:47
PMCR- 2025/02/13
CRDT- 2024/03/14 04:12
PHST- 2023/10/13 00:00 [received]
PHST- 2024/01/26 00:00 [revised]
PHST- 2024/01/29 00:00 [accepted]
PHST- 2025/02/13 00:00 [pmc-release]
PHST- 2024/03/14 06:47 [medline]
PHST- 2024/03/14 06:46 [pubmed]
PHST- 2024/03/14 04:12 [entrez]
AID - 10.1021/acsptsci.3c00281 [doi]
PST - epublish
SO  - ACS Pharmacol Transl Sci. 2024 Feb 13;7(3):693-706. doi: 
      10.1021/acsptsci.3c00281. eCollection 2024 Mar 8.