NEW CARBOHYDRATE BASED DNA BINDERS

这是香农奖，为这项研究提供部分支持

This is a Shannon award providing partial support for the research projects that fall short of the assigned Institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. DESCRIPTION: The principal investigator states that small molecules that bind to DNA frequently have therapeutic utility as antitumor agents because they interfere with DNA processing enzymes and transcription factors and that studies that lead to the generation of new DNA binders are therefore important because they increase the possibility of developing antitumor agents with desirable properties. He notes that carbohydrates are ideal building blocks to use in the design of new DNA binders for several reasons; first, carbohydrates are relatively rigid molecules, which is a significant advantage in binding, second, carbohydrates contain an array of hydroxyls which can be converted to other functional groups that interact with DNA, third, Nature has already provided a set of DNA binding carbohydrates (components of known antitumor agents) to use as starting structures in the design of new DNA binders. The goal of the proposed research is to explore the potential of carbohydrates as scaffolds for the design of new DNA binders. The specific aims are said to be: I. The synthesis and evaluation of carbohydrate mimics of basic region peptide dimers. a) To synthesize alpha-(1-4) linked carbohydrate polymers as mimics for alpha-helical peptides. b) To make bZIP basic region mimics by functionalizing the carbohydrate polymers with basic groups. c) To evaluate the DNA binding properties of both monomers and dimers of the carbohydrate basic region mimics. II. The synthesis and evaluation of functionalized minor groove binders based on the calicheamicin oligosaccharide. a) To develop a carbohydrate scaffold based on the calicheamicin oligosaccharide that can be synthesized rapidly. b) To functionalize the oligosaccharide with functional groups resembling amino acid side chains to increase the binding affinity. III. The synthesis and evaluation of dimers of the calicheamicin A-B-E trisaccharide. a) To synthesize a dimer of the calicheamicin A-B-E trisaccharide. b) To evaluate the binding affinity and specificity. c) To apply the dimerization strategy to creating high affinity carbohydrate-based DNA binders from a simplified carbohydrate scaffold.