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

• Published in: ACS medicinal chemistry letters 2022-06, Vol.13 (6), p.949-954
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00094

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.