Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics

Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics

On the basis of the knowledge that the proline-rich hot spot PPPRPP region of P(151)­PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22phox (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47phox (p47), we designed a mimetic of the tripeptide PPP...

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Veröffentlicht in:ACS medicinal chemistry letters 2022-06, Vol.13 (6), p.949-954
Hauptverfasser: Garsi, Jean-Baptiste, Komjáti, Balázs, Cullia, Gregorio, Fejes, Imre, Sipos, Melinda, Sipos, Zoltán, Fördős, Eszter, Markacz, Piroska, Balázs, Barbara, Lancelot, Nathalie, Berger, Sylvie, Raimbaud, Eric, Brown, David, Vuillard, Laurent-Michel, Haberkorn, Laure, Cukier, Cyprian, Szlávik, Zoltán, Hanessian, Stephen
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container_issue 6
container_start_page 949
container_title ACS medicinal chemistry letters
container_volume 13
creator Garsi, Jean-Baptiste
Komjáti, Balázs
Cullia, Gregorio
Fejes, Imre
Sipos, Melinda
Sipos, Zoltán
Fördős, Eszter
Markacz, Piroska
Balázs, Barbara
Lancelot, Nathalie
Berger, Sylvie
Raimbaud, Eric
Brown, David
Vuillard, Laurent-Michel
Haberkorn, Laure
Cukier, Cyprian
Szlávik, Zoltán
Hanessian, Stephen
description On the basis of the knowledge that the proline-rich hot spot PPPRPP region of P(151)­PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22phox (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47phox (p47), we designed a mimetic of the tripeptide PPP based on NMR and X-ray crystallographic data for the p22(151−161) peptide PPSNPPPRPPA with a peptide construct. Incorporation of the synthetic pseudo-triproline mimetic Pro-Pro-Cyp in a molecule derived from molecular modeling studies led to only a 7-fold diminution in activity in a surface plasmon resonance assay relative to the same molecule containing the natural Pro-Pro-Pro tripeptide. The alternative sequence corresponding to a Pro-Cyp-Pro insertion was inactive. This is a first example of the use of a triproline mimetic to interfere with the formation of the p47–p22 complex, which is critical for the activation of NOX, leading to the production of reactive oxygen species as superoxide anions.
doi_str_mv 10.1021/acsmedchemlett.2c00094
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title Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics
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