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Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation

Cheung, Sheldon T. and Miller, Michelle S. and Pacoma, Reynand and Roland, Jason and Liu, Jian and Schumacher, Andrew M. and Hsieh-Wilson, Linda C. (2017) Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation. ACS Chemical Biology, 12 (12). pp. 3126-3133. ISSN 1554-8929. PMCID PMC5896753. doi:10.1021/acschembio.7b00885.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription Information CentralArticle
Miller, Michelle S.0000-0001-5494-2296
Liu, Jian0000-0001-8552-1400
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Additional Information:© 2017 American Chemical Society. Received: October 13, 2017; Accepted: November 3, 2017; Published: November 3, 2017. We would like to thank the Beckman Institute Laser Resource Center at Caltech for use of the Fluorolog 3 instrument, A. Fisher for providing APS kinase, L. Pedersen for providing Hs3st1 and Sult2b1a/b vectors, and H. Geller for providing the Neu7 astrocyte cell line. This work was supported by grants from the National Institutes of Health (R01 GM093627 (L.C.H.-W.) and NIH/NRSA 5T32 GM07616 (S.T.C.)). The authors declare no competing financial interests.
Funding AgencyGrant Number
NIHR01 GM093627
NIH Predoctoral Fellowship5T32 GM07616
Issue or Number:12
PubMed Central ID:PMC5896753
Record Number:CaltechAUTHORS:20171106-100248113
Persistent URL:
Official Citation:Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation. Sheldon T. Cheung, Michelle S. Miller, Reynand Pacoma, Jason Roland, Jian Liu, Andrew M. Schumacher, and Linda C. Hsieh-Wilson. ACS Chemical Biology 2017 12 (12), 3126-3133. DOI: 10.1021/acschembio.7b00885
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:82975
Deposited By: Tony Diaz
Deposited On:06 Nov 2017 18:39
Last Modified:21 Mar 2022 16:38

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