Rational Design of Small Molecule Inhibitors Targeting the Rac GTPase-p67(phox) Signaling Axis in Inflammation

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2012 Feb 28

PMID 22365606

Citations 24

Authors

Emily E Bosco

Sachin Kumar

Filippo Marchioni

Jacek Biesiada

Miroslaw Kordos

Kathleen Szczur

Jarek Meller

William Seibel

Ariel Mizrahi

Edgar Pick

Marie-Dominique Filippi

Yi Zheng

Affiliations

Soon will be listed here.

Abstract

The NADPH oxidase enzyme complex, NOX2, is responsible for reactive oxygen species production in neutrophils and has been recognized as a key mediator of inflammation. Here, we have performed rational design and in silico screen to identify a small molecule inhibitor, Phox-I1, targeting the interactive site of p67(phox) with Rac GTPase, which is a necessary step of the signaling leading to NOX2 activation. Phox-I1 binds to p67(phox) with a submicromolar affinity and abrogates Rac1 binding and is effective in inhibiting NOX2-mediated superoxide production dose-dependently in human and murine neutrophils without detectable toxicity. Medicinal chemistry characterizations have yielded promising analogs and initial information of the structure-activity relationship of Phox-I1. Our studies suggest the potential utility of Phox-I class inhibitors in NOX2 oxidase inhibition and present an application of rational targeting of a small GTPase-effector interface.

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