Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation

ACS Chemical Biology
Sheldon T CheungLinda C Hsieh-Wilson

Abstract

Glycosaminoglycans (GAGs) play critical roles in diverse processes ranging from viral infection to neuroregeneration. Their regiospecific sulfation patterns, which are generated by sulfotransferases, are key structural determinants that underlie their biological activity. Small-molecule modulators of these sulfotransferases could serve as powerful tools for understanding the physiological functions of GAGs, as well as potential therapeutic leads for human diseases. Here, we report the development of the first cell-permeable, small-molecule inhibitor selective for GAG sulfotransferases, which was obtained using a high-throughput screen targeted against Chst15, the sulfotransferase responsible for biosynthesis of chondroitin sulfate-E (CS-E). We demonstrate that the molecule specifically inhibits GAG sulfotransferases in vitro, decreases CS-E and overall sulfation levels on cell-surface and secreted chondroitin sulfate proteoglycans (CSPGs), and reverses CSPG-mediated inhibition of axonal growth. These studies pave the way toward a new set of pharmacological tools for interrogating GAG sulfation-dependent processes and may represent a novel therapeutic approach for neuroregeneration.

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Citations

Mar 30, 2019·British Journal of Pharmacology·James A DuncanJessica C F Kwok
Jan 9, 2019·Frontiers in Cell and Developmental Biology·Seyedeh Maryam Alavi Naini, Nadia Soussi-Yanicostas
Oct 3, 2018·Seminars in Cell & Developmental Biology·Damien TestaAriel A Di Nardo
Dec 5, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Heidi N du PreezJohnson Lin

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