A closer look into NADPH oxidase inhibitors : Validation and insight into their mechanism of action
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved..
NADPH-oxidases (NOXs) purposefully produce reactive-oxygen-species (ROS) and are found in most kingdoms of life. The seven human NOXs are each characterized by a specific expression profile and a fine regulation to spatio-temporally tune ROS concentration in cells and tissues. One of the best known roles for NOXs is in host protection against pathogens but ROS themselves are important second messengers involved in tissue regeneration and the modulation of pathways that induce and sustain cell proliferation. As such, NOXs are attractive pharmacological targets in immunomodulation, fibrosis and cancer. We have studied an extensive number of available NOX inhibitors, with the specific aim to identify bona fide ligands versus ROS-scavenging molecules. Accordingly, we have established a comprehensive platform of biochemical and biophysical assays. Most of the investigated small molecules revealed ROS-scavenging and/or assay-interfering properties to various degrees. A few compounds, however, were also demonstrated to directly engage one or more NOX enzymes. Diphenylene iodonium was found to react with the NOXs' flavin and heme prosthetic groups to form stable adducts. We also discovered that two compounds, VAS2870 and VAS3947, inhibit NOXs through the covalent alkylation of a cysteine residue. Importantly, the amino acid involved in covalent binding was found to reside in the dehydrogenase domain, where the nicotinamide ring of NADPH is bound. This work can serve as a springboard to guide further development of bona fide ligands with either agonistic or antagonistic properties toward NOXs.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2020 |
---|---|
Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
---|---|
Enthalten in: |
Redox biology - 32(2020) vom: 01. Mai, Seite 101466 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Reis, Joana [VerfasserIn] |
---|
Links: |
---|
Themen: |
53-59-8 |
---|
Anmerkungen: |
Date Completed 18.06.2021 Date Revised 18.06.2021 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1016/j.redox.2020.101466 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM306982773 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM306982773 | ||
003 | DE-627 | ||
005 | 20231225124552.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2020 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.redox.2020.101466 |2 doi | |
028 | 5 | 2 | |a pubmed24n1023.xml |
035 | |a (DE-627)NLM306982773 | ||
035 | |a (NLM)32105983 | ||
035 | |a (PII)S2213-2317(20)30126-9 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Reis, Joana |e verfasserin |4 aut | |
245 | 1 | 2 | |a A closer look into NADPH oxidase inhibitors |b Validation and insight into their mechanism of action |
264 | 1 | |c 2020 | |
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 Completed 18.06.2021 | ||
500 | |a Date Revised 18.06.2021 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved. | ||
520 | |a NADPH-oxidases (NOXs) purposefully produce reactive-oxygen-species (ROS) and are found in most kingdoms of life. The seven human NOXs are each characterized by a specific expression profile and a fine regulation to spatio-temporally tune ROS concentration in cells and tissues. One of the best known roles for NOXs is in host protection against pathogens but ROS themselves are important second messengers involved in tissue regeneration and the modulation of pathways that induce and sustain cell proliferation. As such, NOXs are attractive pharmacological targets in immunomodulation, fibrosis and cancer. We have studied an extensive number of available NOX inhibitors, with the specific aim to identify bona fide ligands versus ROS-scavenging molecules. Accordingly, we have established a comprehensive platform of biochemical and biophysical assays. Most of the investigated small molecules revealed ROS-scavenging and/or assay-interfering properties to various degrees. A few compounds, however, were also demonstrated to directly engage one or more NOX enzymes. Diphenylene iodonium was found to react with the NOXs' flavin and heme prosthetic groups to form stable adducts. We also discovered that two compounds, VAS2870 and VAS3947, inhibit NOXs through the covalent alkylation of a cysteine residue. Importantly, the amino acid involved in covalent binding was found to reside in the dehydrogenase domain, where the nicotinamide ring of NADPH is bound. This work can serve as a springboard to guide further development of bona fide ligands with either agonistic or antagonistic properties toward NOXs | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a NADPH oxidase | |
650 | 4 | |a NOX | |
650 | 4 | |a ROS scavengers | |
650 | 4 | |a Reactive oxygen species | |
650 | 7 | |a Reactive Oxygen Species |2 NLM | |
650 | 7 | |a NADP |2 NLM | |
650 | 7 | |a 53-59-8 |2 NLM | |
650 | 7 | |a NADPH Oxidases |2 NLM | |
650 | 7 | |a EC 1.6.3.- |2 NLM | |
700 | 1 | |a Massari, Marta |e verfasserin |4 aut | |
700 | 1 | |a Marchese, Sara |e verfasserin |4 aut | |
700 | 1 | |a Ceccon, Marta |e verfasserin |4 aut | |
700 | 1 | |a Aalbers, Friso S |e verfasserin |4 aut | |
700 | 1 | |a Corana, Federica |e verfasserin |4 aut | |
700 | 1 | |a Valente, Sergio |e verfasserin |4 aut | |
700 | 1 | |a Mai, Antonello |e verfasserin |4 aut | |
700 | 1 | |a Magnani, Francesca |e verfasserin |4 aut | |
700 | 1 | |a Mattevi, Andrea |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Redox biology |d 2013 |g 32(2020) vom: 01. Mai, Seite 101466 |w (DE-627)NLM22743725X |x 2213-2317 |7 nnns |
773 | 1 | 8 | |g volume:32 |g year:2020 |g day:01 |g month:05 |g pages:101466 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.redox.2020.101466 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 32 |j 2020 |b 01 |c 05 |h 101466 |