Heparanase (HPA) is a critical enzyme involved in the remodeling of the extracellular matrix (ECM), and its elevated expression has been linked with diseases such as various types of cancer and inflammation. The detection of heparanase enzymatic activity holds tremendous value in the study of the cellular microenvironment, and search of molecular therapeutics targeting heparanase, however, no structurally defined probes are available for the detection of heparanase activity. Here we present the development of the first ultrasensitive fluorogenic small-molecule probe for heparanase enzymatic activity tuning the electronic effect of the substrate. The probe exhibits a 756-fold fluorescence turn-on response in the presence of human heparanase, allowing one-step detection of heparanase activity in real-time with a picomolar detection limit. The high sensitivity and robustness of the probe are exemplified in a high-throughput screening assay for heparanase inhibitors.
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| http://dx.doi.org/10.1039/d0sc04872k | DOI Listing |
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View Article and Find Full Text PDFChemical toolbox to interrogate Heparanase-1 activity.
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Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. Electronic address:
The development of a robust chemical toolbox to interrogate the activity of heparanase-1 (HPSE-1), an endo-β-d-glucuronidase and the only known enzyme that cleaves heparan sulfate (HS), has become critically important. The primary function of HPSE-1, cleaving HS side chains from heparan sulfate proteoglycans (HSPGs), regulates the integrity of the extracellular matrix (ECM) and the bioavailability of active, heparan sulfate-binding partners such as enzymes, growth factors, chemokines, and cytokines. HPSE-1 enzymatic activity is strictly regulated and has been found to play fundamental roles in pathophysiological processes.
View Article and Find Full Text PDFHeparanase-1 (HPSE-1), an endo-β-D-glucuronidase, is an extracellular matrix (ECM) remodeling enzyme that degrades heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPGs). HPSE-1 functions to remodel the ECM and thereby disseminate cells, liberate HS-bound bioactive molecules, and release biologically active HS fragments. Being the only known enzyme for the cleavage of HS, HPSE-1 regulates a number of fundamental cellular processes including cell migration, cytokine regulation, angiogenesis, and wound healing.
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