biostudies-literatureGarsi JBNatural Sciences and Engineering Research Council of Canada949-954https://www.ebi.ac.uk/biostudies/studies/S-EPMC9190036biostudies-literatureUnknown13(6)On the basis of the knowledge that the proline-rich hot spot <b>PPP</b>RPP region of P(151)PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22^phox (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47^phox (p47), we designed a mimetic of the tripeptide <b>PPP</b> based on NMR and X-ray crystallographic data for the p22(151-161) peptide PPSN<b>PPP</b>RPPA 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.ACS medicinal chemistry lettersTargeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics.PMC9190036IRCPJ 531309 - 17Szlavik ZLancelot NCullia GFordos ESipos ZVuillard LMBalazs BBrown DFejes IMarkacz PKomjati BCukier CGarsi JBRaimbaud EHanessian SSipos MBerger SHaberkorn LfalseTargeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics.On the basis of the knowledge that the proline-rich hot spot <b>PPP</b>RPP region of P(151)PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22^phox (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47^phox (p47), we designed a mimetic of the tripeptide <b>PPP</b> based on NMR and X-ray crystallographic data for the p22(151-161) peptide PPSN<b>PPP</b>RPPA 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.2022-01-01T00:00:00Z2022 Jun2025-04-27T02:21:11.418Z2025-04-06T18:32:36.752ZS-EPMC91900363570714010.1021/acsmedchemlett.2c00094