Structure-Based Identification of Kelch-like ECH-Associated Protein 1 as a Pharmacological Target of Electrophile-Containing Catechol-O-Methyltransferase Inhibitors
© 2024 American Chemical Society..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
---|---|
Enthalten in: |
ACS pharmacology & translational science - 7(2024), 3 vom: 08. März, Seite 693-706 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Wang, Ping [VerfasserIn] |
---|
Links: |
---|
Themen: |
---|
Anmerkungen: |
Date Revised 15.03.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
---|
doi: |
10.1021/acsptsci.3c00281 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM369713923 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM369713923 | ||
003 | DE-627 | ||
005 | 20240315234213.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240315s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1021/acsptsci.3c00281 |2 doi | |
028 | 5 | 2 | |a pubmed24n1330.xml |
035 | |a (DE-627)NLM369713923 | ||
035 | |a (NLM)38481699 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Wang, Ping |e verfasserin |4 aut | |
245 | 1 | 0 | |a Structure-Based Identification of Kelch-like ECH-Associated Protein 1 as a Pharmacological Target of Electrophile-Containing Catechol-O-Methyltransferase Inhibitors |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Revised 15.03.2024 | ||
500 | |a published: Electronic-eCollection | ||
500 | |a Citation Status PubMed-not-MEDLINE | ||
520 | |a © 2024 American Chemical Society. | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
700 | 1 | |a Li, Yang |e verfasserin |4 aut | |
700 | 1 | |a Yang, Jinyi |e verfasserin |4 aut | |
700 | 1 | |a Li, Ziwen |e verfasserin |4 aut | |
700 | 1 | |a Ren, Xintong |e verfasserin |4 aut | |
700 | 1 | |a Meng, Qingshi |e verfasserin |4 aut | |
700 | 1 | |a Li, Pengfei |e verfasserin |4 aut | |
700 | 1 | |a Qin, Luzhe |e verfasserin |4 aut | |
700 | 1 | |a Li, Wei |e verfasserin |4 aut | |
700 | 1 | |a Xie, Yuting |e verfasserin |4 aut | |
700 | 1 | |a Hou, Nannan |e verfasserin |4 aut | |
700 | 1 | |a Huang, Niu |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t ACS pharmacology & translational science |d 2018 |g 7(2024), 3 vom: 08. März, Seite 693-706 |w (DE-627)NLM294010823 |x 2575-9108 |7 nnns |
773 | 1 | 8 | |g volume:7 |g year:2024 |g number:3 |g day:08 |g month:03 |g pages:693-706 |
856 | 4 | 0 | |u http://dx.doi.org/10.1021/acsptsci.3c00281 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 7 |j 2024 |e 3 |b 08 |c 03 |h 693-706 |