Alkyne derivatives of isocoumarins as clickable activity-based probes for serine proteases.

Abstract:

:Activity-based probes (ABPs) have found increasing use in functional proteomics studies. Recently, ABPs that can be employed in combination with click chemistry gained particular attention due to their flexible application in vitro and in vivo. Moreover, there is a continuous need for new ABPs that target small subsets of enzymes. We here report novel clickable ABPs based on the 4-chloro-isocoumarin (IC) electrophile, a mechanism-based inhibitor scaffold that covalently binds serine proteases. We describe the synthesis of a small library of IC ABPs containing an alkyne function and a set of diverse selectivity elements. The different substituents on the IC structure determine which proteases are bound, showing good correlation with the preferred substrate preferences. The IC ABPs can detect their target proteases in a proteome background in a sensitive manner (down to 0.007% of total protein). Furthermore, we show activity-dependent and selective labeling of endogenous proteases in a tissue proteome. These ICs therefore represent a valuable extension to already existing ABPs for serine proteases and may be instrumental in future elucidation of serine protease functions.

journal_name

Bioorg Med Chem

authors

Haedke U,Götz M,Baer P,Verhelst SH

doi

10.1016/j.bmc.2011.03.014

subject

Has Abstract

pub_date

2012-01-15 00:00:00

pages

633-40

issue

2

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(11)00195-7

journal_volume

20

pub_type

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