Unknown

Dataset Information

0

Rational design of small molecule inhibitors targeting the Rac GTPase-p67(phox) signaling axis in inflammation.


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.

SUBMITTER: Bosco EE 

PROVIDER: S-EPMC3292765 | BioStudies | 2012-01-01

REPOSITORIES: biostudies

Similar Datasets

2015-01-01 | S-EPMC4316792 | BioStudies
2012-01-01 | S-EPMC3280886 | BioStudies
2011-01-01 | S-EPMC3220462 | BioStudies
2016-01-01 | S-EPMC4820915 | BioStudies
1000-01-01 | S-EPMC2966130 | BioStudies
2002-01-01 | S-EPMC126167 | BioStudies
2008-01-01 | S-EPMC2442356 | BioStudies
2012-01-01 | S-EPMC3326000 | BioStudies
2008-01-01 | S-EPMC2755574 | BioStudies
2007-01-01 | S-EPMC1955831 | BioStudies