Year: 2022
Type: article
Abstract: Heparanase (HPSE) is an endo-β-glucuronidase involved in extracellular matrix remodeling in rapidly healing tissues, most cancers and inflammation, and viral infection. Its importance as a therapeutic target warrants further study, but such is hampered by a lack of research tools. To expand the toolkits for probing HPSE enzymatic activity, we report the design of a substrate scaffold for HPSE comprised of a disaccharide substrate appended with a linker, capable of carrying cargo until being cleaved by HPSE. Here exemplified as a fluorogenic, coumarin-based imaging probe, this scaffold can potentially expand the availability of HPSE-responsive imaging or drug delivery tools using a variety of imaging moieties or other cargo. We show that electronic tuning of the scaffold provides a robust response to HPSE while simplifying the structural requirements of the attached cargo. Molecular docking and modeling suggest a productive probe/HPSE binding mode. These results further support the hypothesis that the reactivity of these HPSE-responsive probes is predominantly influenced by the electron density of the aglycone. This universal HPSE-activatable scaffold will greatly facilitate future development of HPSE-responsive probes and drugs.
Source: Bioconjugate Chemistry
Authors: Kelton A. Schleyer, Jun Liu, Zixin Chen, Zhishen Wang, Yuzhao Zhang, Junxiang Zuo, Alberto Jimenez Ybargollin, Hua Guo, Lina Cui
Language: English
Subfield: Spectroscopy
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Defense, McKnight Foundation, Florida Department of Health, University of Florida, National High Magnetic Field Laboratory, National Institutes of Health, University of Florida Health, National Institute of General Medical Sciences, National Institute of Biomedical Imaging and Bioengineering, Division of Materials Research, High Magnetic Field Laboratory, Chinese Academy of Sciences, Congressionally Directed Medical Research Programs
Awards: G1138554163, National High Magnetic Field Laboratory Renewal 2018-2022, G2040153736, G2153269556, G2336362177, Acquisition of a Q Exactive HF Hybrid Quadrupole-Orbitrap, G354028113, G3560959519, DEVELOPMENT OF DIAGNOSTIC TOOLS FOR METASTATIC MELANOMA VIA IMAGING OF HEPARANASE ACTIVITY, G410635398, G4119534169, G5597825783, G5850682332, NMR console upgrade for structural biology and metabolomics, G6010147111, National Resource For Advanced NMR Technology, G746412539, Improved NMR Technology for Natural Products and Metabolomics., G8980305068, G9000090720
OpenAlex ID: W4308531497