Small molecules that bind to biological receptors are extremely valuable both as leads for drug design and as model systems for understanding molecular recognition events. The goal of the proposed research is to explore the potential of functionalized carbohydrates as mimics of peptides that bind to biological receptors. Accordingly, specific functionalized carbohydrates designed to mimic certain peptide alpha helices and beta strands will be synthesized and screened for binding. In addition, because the probability of identifying a carbohydrate lead that binds to a biological receptor increases with the number of compounds that can be made, methods to synthesize and screen resin-bound carbohydrates for binding to protein receptors are also proposed.
The specific aims are outlined below: 1. The design and synthesis of carbohydrate mimics of basic region peptides and peptide dimers that bind to DNA. (1-4)-linked carbohydrate polymers functionalized with amino and guanidinium side chains will be synthesized and evaluated for their ability to mimic alpha helical basic region peptides that bind to DNA. 2. Design and synthesis of a carbohydrate to mimic beta-strand pep tides that inhibit thrombin. A disaccharide mimic of a thrombin inhibitor will be synthesized and evaluated for its ability to inhibit thrombin. 3. Development of a solid-phase combinatorial approach to identifying carbohydrate-based molecules that bind to biological receptors. Methods to synthesize deprotected carbohydrates on the solid phase will be developed. Assays to detect the binding of resin-bound carbohydrates to biological receptors will be developed. The synthetic methods and the assay will ultimately be applied to the synthesis and screening of a combinatorial library of carbohydrate molecules.
