An ongoing area of interest is in the development of agents that either block heparan sulfate-protein interactions or that exploit heparan sulfate proteoglycans as portals of entry for delivery of high molecular weight cargo into cells and tissues. In collaboration with Yitzhak Tor's group at UCSD, we have tested guanidinoglycosides as carriers. Guanidinoneomycin can carry large bioactive molecules across cell membranes. Delivery occurs at nanomolar transporter concentrations and under these conditions depends entirely on cell surface heparan sulfate proteoglycans. Conjugation of guanidinoneomycin to streptavidin provides a useful agent to detect cell surface proteoglycans. Conjugation to the plant toxin saporin, a ribosome-inactivating agent, results in proteoglycan-dependent cell toxicity, providing a tool for selecting mutants and potentially for chemotherapy. Conjugation of gunidinoneomycin to lysosomal enzymes allows reconstitution of lysosomal function in cells derived from patients with mucopolysaccharidoses (MPS). Recent work has shown that conjugation facilitates delivery to cells in the brain, opening up the possibility of developing tools for treating various lysosomal storage disorders that affect the brain.
Hereditary Multiple Exostosis (HME) is a dominant disorder characterized by the appearance of osteochondromas along the growth plate of endochondral bones. The disease arises from heterozygous mutations in Ext1 or Ext2, which encod e subunits of the copolymerase complex responsible for the formation of heparan sulfate. We have an ongoing project to discover and characterize potential drugs for altering the expression of heparan sulfate as a therapeutic approach for treating HME. Drug-like agents have been found that modulate heparan sulfate formation. Current studies focus on their mechanism of action and optimization.
Schuksz, M., Fuster, M.M., Brown, J.R., Crawford, B.E., Ditto, D.P., Lawrence, R., Glass, C.A., Wang, L., Tor, Y., and Esko, J.D. (2008) Surfen, a small molecule antagonist of heparan sulfate. Proc. Natl. Acad. Sci. 105:13075-13080
Weiss, R.J., Gordts, P.L.S.M., Le, D., Xu, D., Esko, J.D. and Tor, Y. (2015) Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions. Chem. Sci. 6:5984-5993.
Hamill, K.M., McCoy, L.S., Wexselblatt, E., Esko, J.D. and Tor, Y. (2016) Polymyxins facilitate entry into mammalian cells. Chem. Sci. 7:5059-5068.
Hamill, K.M., Wexselblatt, E., Tong, W., Esko, J.D. and Tor, Y. (2016) Delivery of an active lysosomal enzyme using GNeosomes. J. Mater. Chem. B. 4:5794-5797.