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Issue 34, 2013
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Tuning activity-based probe selectivity for serine proteases by on-resin ‘click’ construction of peptide diphenyl phosphonates

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Abstract

Activity-based probes (ABPs) are powerful tools for functional proteomics studies. Their selectivity can be influenced by modification of a recognition element that interacts with pockets near the active site. For serine proteases there are a limited number of simple and efficient synthetic procedures for the development of selective probes. Here we describe a new synthetic route combining solid and solution phase chemistries to generate a small library of diphenyl phosphonate probes. Building blocks carrying a P1 recognition element and an electrophilic phosphonate warhead were prepared in solution and ‘clicked’ on-resin onto a tripeptide. We show the ability to modulate the activity and selectivity of diphenyl phosphonate ABPs and demonstrate activity-dependent labeling of endogenous proteases within a tissue proteome. The herein described synthetic approach therefore serves as a valuable method for rapid diversification of serine protease ABPs.

Graphical abstract: Tuning activity-based probe selectivity for serine proteases by on-resin ‘click’ construction of peptide diphenyl phosphonates

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Publication details

The article was received on 01 May 2013, accepted on 09 Jul 2013 and first published on 09 Jul 2013


Article type: Paper
DOI: 10.1039/C3OB40907D
Citation: Org. Biomol. Chem., 2013,11, 5714-5721
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    Tuning activity-based probe selectivity for serine proteases by on-resin ‘click’ construction of peptide diphenyl phosphonates

    S. Serim, S. V. Mayer and S. H. L. Verhelst, Org. Biomol. Chem., 2013, 11, 5714
    DOI: 10.1039/C3OB40907D

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