The long-term goal of this program is to advance our knowledge of ligand-cell surface interactions and apply it to the design, synthesis and implementation of new cellular delivery agents. Towards this end, we have synthesized a series of guanidinoglycoside transporters by derivatizing aminoglycosides and have shown that various cell lines bind and take up the compounds efficiently via negatively-charged cell-surface proteoglycans containing the glycan, heparan sulfate. The guanidinoglycosides act as transporters, enhancing the cellular uptake of otherwise impermeable molecules.
The specific aims provide a comprehensive approach for the design and synthesis of new guanidinoglycosides, assessment of their cellular uptake and localization in different cell lines, and their evaluation of their ability to deliver cargos of therapeutic potential:
AIM 1. Synthesize systematically modified guanidinoglycosides and evaluate their cellular uptake. To understand comprehensively the impact of the overall charge, as well as the distribution and three- dimensional projection of guanidinium groups, a series of derivatives will be synthesized. A structure-activity-relationship will be developed using cell-based assays for binding and uptake with the objective of identifying the most effective delivery vehicle.
AIM 2. Evaluate binding and uptake of guanidinoglycosides in different cell types. The binding and uptake of guanidinoglycosides in human and murine tumor cells and in human fibroblasts will be investigated and compared to the mechanisms in CHO cells.
AIM 3. Synthesize and evaluate cellular uptake of guanidinoglycoside-drug conjugates. The most promising guanidinium-containing derivatives will be conjugated to molecular cargos (including small molecules and high MW proteins) and their cellular uptake will be evaluated. We will examine if delivery of toxins can be exploited to block tumor growth and if lysosomal storage deficiency can be corrected by enzyme replacement mediated via transporters. A mechanism-based development of transduction scaffolds will identify lead structures and facilitate the development of useful drug delivery vehicles. New molecular delivery vehicles will expand the repertoire of tools available to control the localization and release of therapeutics. The proposed work thus aims to acquire information about new transporters and provide a platform for treating disease.
| Weiss, Ryan J; Esko, Jeffrey D; Tor, Yitzhak (2017) Targeting heparin and heparan sulfate protein interactions. Org Biomol Chem 15:5656-5668 |
| Hamill, Kristina M; McCoy, Lisa S; Wexselblatt, Ezequiel et al. (2016) Polymyxins Facilitate Entry into Mammalian Cells. Chem Sci 7:5059-5068 |
| Wexselblatt, Ezequiel; Esko, Jeffrey D; Tor, Yitzhak (2015) GNeosomes: Highly Lysosomotropic Nanoassemblies for Lysosomal Delivery. ACS Nano 9:3961-8 |
| Weiss, Ryan J; Gordts, Philip L S M; Le, Dzung et al. (2015) Small molecule antagonists of cell-surface heparan sulfate and heparin-protein interactions. Chem Sci 6:5984-5993 |
| Wexselblatt, Ezequiel; Esko, Jeffrey D; Tor, Yitzhak (2014) On guanidinium and cellular uptake. J Org Chem 79:6766-74 |
| Inoue, Makoto; Wexselblatt, Ezequiel; Esko, Jeffrey D et al. (2014) Macromolecular uptake of alkyl-chain-modified guanidinoglycoside molecular transporters. Chembiochem 15:676-80 |
| Lawrence, Roger; Brown, Jillian R; Lorey, Fred et al. (2014) Glycan-based biomarkers for mucopolysaccharidoses. Mol Genet Metab 111:73-83 |
| Frolov, Ludmila; Dix, Andrew; Tor, Yitzhak et al. (2013) Direct observation of aminoglycoside-RNA binding by localized surface plasmon resonance spectroscopy. Anal Chem 85:2200-7 |
| Inoue, Makoto; Tong, Wenyong; Esko, Jeffrey D et al. (2013) Aggregation-mediated macromolecular uptake by a molecular transporter. ACS Chem Biol 8:1383-8 |
| Kowalewski, Bjorn; Lamanna, William C; Lawrence, Roger et al. (2012) Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase activity and mucopolysaccharidosis in mice. Proc Natl Acad Sci U S A 109:10310-5 |
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