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

Autor:	Jean-Baptiste Garsi, Balázs Komjáti, Gregorio Cullia, Imre Fejes, Melinda Sipos, Zoltán Sipos, Eszter Fördős, Piroska Markacz, Barbara Balázs, Nathalie Lancelot, Sylvie Berger, Eric Raimbaud, David Brown, Laurent-Michel Vuillard, Laure Haberkorn, Cyprian Cukier, Zoltán Szlávik, Stephen Hanessian
Rok vydání:	2022
Předmět:	protein-protein interaction Medicinal and Biomolecular Chemistry Triproline mimetic cytosolic proteins Organic Chemistry Drug Discovery Pharmacology and Pharmaceutical Sciences Biochemistry Biotechnology hot spots
Zdroj:	ACS medicinal chemistry letters, vol 13, iss 6 ACS Med Chem Lett
ISSN:	1948-5875
Popis:	[Image: see text] 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 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 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2aa70b14a5bdfbbdfe94d8e9fe7ef2af https://doi.org/10.1021/acsmedchemlett.2c00094 Zobrazit plný text záznamu