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

Jean-Baptiste Garsi¹, Balázs Komjáti², Gregorio Cullia¹

¹Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montréal, QC H2V 0B3, Canada.

ACS Medicinal Chemistry Letters

|June 16, 2022

Summary

Researchers developed a novel triproline mimetic to disrupt the p47-p22 complex, crucial for NOX activation and reactive oxygen species production. This mimetic offers a new strategy for interfering with this critical biological pathway.

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Area of Science:

Biochemistry
Molecular Biology
Pharmacology

Background:

The p47^phox (p47) protein's SH3 domain binds to proline-rich motifs, such as the P(151)PSNPPPRPP(160) region of p22^phox (p22).
This interaction is vital for the assembly of the NADPH oxidase (NOX) complex, which generates superoxide anions.

Purpose of the Study:

To design and synthesize a mimetic of the triproline (PPP) motif found in p22^phox.
To evaluate the efficacy of this mimetic in inhibiting the p47-p22 interaction and NOX activation.

Main Methods:

Utilized NMR and X-ray crystallographic data of the p22(151-161) peptide for designing the mimetic.
Incorporated a synthetic pseudo-triproline mimetic (Pro-Pro-Cyp) into a molecular construct.
Assessed binding activity using surface plasmon resonance (SPR) assays.

Main Results:

The Pro-Pro-Cyp mimetic showed only a 7-fold decrease in activity compared to the natural Pro-Pro-Pro tripeptide in SPR assays.
An alternative Pro-Cyp-Pro insertion sequence was found to be inactive.
This represents the first successful use of a triproline mimetic to disrupt the p47-p22 complex.

Conclusions:

A novel triproline mimetic effectively interferes with the p47-p22 complex formation.
This mimetic holds potential for modulating NOX enzyme activity and reactive oxygen species production.
The study provides a new tool for investigating NOX-related biological processes.