Post-Doctoral Auburn University 1996; Ph.D. Auburn University 1996; B.A. University of South Florida 1992

Among the most prominent structures that arise from a survey of the molecules of nature are the nucleosides. Such compounds can serve as energy storage units, enzyme cofactors, phosphate reservoirs, codes for genetic information, etc. With this in mind, it is not surprising that structural modifications of the nucleoside framework can result in useful molecules.

The primary focus in the Seley-Radtke group involves the discovery, design and synthesis of nucleoside/nucleotide and heterocyclic enzyme inhibitors for use as medicinal agents with chemotherapeutic emphasis in the areas of anticancer, antiviral, antibiotic and antiparasitic targets. One project involves the use of flexible inhibitors ('fleximers') in drug design as a powerful technique to confront the challenges presented by the development of drug resistance in currently used therapeutics. These analogues arise by splitting the purine moiety into its individual components. This will impart a degree of flexibility, thereby allowing each component to fit more readily into a flexible enzyme binding site while still maintaining the molecular elements needed for recognition.

A second project involves use of extended nucleotide base pairs to explore DNA and RNA structure and function. Using a cross-disciplinary chemical biology approach, synthetic organic chemistry is augmented by the use of enzymatic assays to survey the effectiveness of the potential drug candidates. Investigations also involve surveying polymerase fidelity with modified nucleotide analogues that possess unique structural advantages designed for enhanced recognition, as well as increased helix stability.

Another focus area employs structure activity relationship (SAR) algorithms and docking modeling for the biological enhancement of lead compounds, as well as to distinguish and develop synergistic inhibitors for biosynthetic pathways through a combination of synthetic, biological screening, mechanistic and structure-based drug design techniques. A more traditional aspect of the research carried out involves the design and synthesis of a series of purine-based nucleosides where the ribofuranose moiety is attached at N-3 rather than the traditional N-9 position. These modified carbocyclic nucleosides should exert their medicinal effect by the inhibition of several key enzymes, S-adenosylhomocysteine hydrolase and/or DNA methyltransferase, with sites set on inducing tumor cell differentiation.

Other medicinal targets being pursued include the synthesis and biophysical evaluation of a focused series of shape-modified tricyclic nucleosides being studied for nucleoside transporter recognition in parasites. Synthetic approaches involve the discovery of unique strategies to solve design challenges using state of the art organic chemistry techniques, including protection/deprotection motifs, enzymatic resolution of enantiomeric mixtures, functional group manipulation, and template directed organometallics for the construction of modified heterocycles, carbohydrates and carbocyclic moieties.