Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 88, Issue -, Pages 28-33Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.06.040
Keywords
Redox-based probes; Redox biology; Reactive oxygen species; Phosphatases; Bioconjugation; Nucleophile-based therapeutics
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Funding
- Camile Henry Dreyfus Teacher Scholar Award
- American Heart Association Scientist Development Award [0835419N]
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Reversible oxidation of protein tyrosine phosphatases (PTPs) has emerged as an important regulatory mechanism whereby reactive oxygen species (ROS) inactivates the PTP and promotes phosphorylation and induction of the signaling cascade. The lack of sensitive and robust methods to directly detect oxidized PTPs has made it difficult to understand the effects that PTP oxidative inactivation play in redox signaling. We report the use of redox-based probes to directly detect oxidized PTPs in a cellular context, which highlights the importance of direct approaches to assist in the study of physiological and pathophysiological PTP activity in redox regulation. We also demonstrate, as a proof-of-concept, that these redox-based probes serve as prototypes for the design and development of a new class of inhibitors for phosphatases. We envision a nucleophile reacting with the oxidized inactive catalytic cysteine to generate an irreversible thioether adduct which prevents the phosphatase from being reactivated and ultimately fortifies the signaling cascade. Our results reveal the potential of translation of our redox-based probes, which are used to understand redox cell circuitry and disease biology, to small-molecule nucleophile-based inhibitors, which may treat diseases associated with redox stress. This may have implications in the treatment of type 2 diabetes and cancer. (C) 2014 Elsevier Masson SAS. All rights reserved.
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