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 Chemjournal_title
Bioorganic & medicinal chemistryauthors
Haedke U,Götz M,Baer P,Verhelst SHdoi
10.1016/j.bmc.2011.03.014subject
Has Abstractpub_date
2012-01-15 00:00:00pages
633-40issue
2eissn
0968-0896issn
1464-3391pii
S0968-0896(11)00195-7journal_volume
20pub_type
杂志文章abstract::A series of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists was prepared. Affinity for the NMDA receptor was determined by binding assays using the specific radioligand [3H] (2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid (CG...
journal_title:Bioorganic & medicinal chemistry
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journal_title:Bioorganic & medicinal chemistry
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journal_title:Bioorganic & medicinal chemistry
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