Issue 5, 2015

Probing the target-specific inhibition of sensitized protein tyrosine phosphatases with biarsenical probes

Abstract

Selective control of enzyme activity is critical for elucidating the roles of specific proteins in signaling pathways. One potential means for developing truly target-specific inhibitors involves the use of protein engineering to sensitize a target enzyme to inhibition by a small molecule that does not inhibit homologous wild-type enzymes. Previously, it has been shown that protein tyrosine phosphatases (PTPs) can be sensitized to inhibition by a biarsenical probe, FlAsH-EDT2, which inhibits PTP activity by specifically binding to cysteine residues that have been introduced into catalytically important regions. In the present study, we developed an array of biarsenical probes, some newly synthesized and some previously reported, to investigate for the first time the structure–activity relationships for PTP inhibition by biarsenicals. Our data show that biarsenical probes which contain substitutions at the 2′ and 7′ positions are more effective than FlAsH-EDT2 at inhibiting sensitized PTPs. The increased potency of 2′,7′-substituted probes was observed when PTPs were assayed with both para-nitrophenylphosphate and phosphopeptide PTP substrates and at multiple probe concentrations. The data further indicate that the enhanced inhibitory properties are the result of increased binding affinity between the 2′,7′-substituted biarsenical probes and sensitized PTPs. In addition we provide previously unknown physicochemical and stability data for various biarsenical probes.

Graphical abstract: Probing the target-specific inhibition of sensitized protein tyrosine phosphatases with biarsenical probes

Supplementary files

Article information

Article type
Paper
Submitted
23 Oct 2014
Accepted
25 Nov 2014
First published
25 Nov 2014

Org. Biomol. Chem., 2015,13, 1395-1403

Author version available

Probing the target-specific inhibition of sensitized protein tyrosine phosphatases with biarsenical probes

A. Pomorski, J. Adamczyk, A. C. Bishop and A. Krężel, Org. Biomol. Chem., 2015, 13, 1395 DOI: 10.1039/C4OB02256D

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements