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Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics
- 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
- et al.
Published Web Location
https://doi.org/10.1021/acsmedchemlett.2c00094Abstract
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.
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