Another project focuses on exploiting heparan sulfate proteoglycans expressed on the cell surface for delivery of high molecular weight cargo. In collaboration with Yitzhak Tor's group at UCSD, we have tested analogs of aminoglycosides in which the amino groups were converted to guanidinium groups. A derivative of the aminoglycoside antibiotic neomycin can carry large (>300 kDa) 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 guanidino-neomycin to the plant toxin saporin, a ribosome-inactivating agent, results in proteoglycan-dependent cell toxicity. Conjugation of gunidinoneomycin to lysosomal enzymes allows reconstitution of lysosomal function in fibroblasts derived from patients with mucopolysaccharidoses (MPS).
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, subunits of the copolymerase complex reponsible for the formation of heparan sulfate. Recently, we have become interested in the discovery of drugs for altering the expression of heparan sulfate as a potential therapeutic approach for treating HME. Towards this end, we have developed high throughput screening methods to identify drug-like compounds.