|Seley-Radtke Research Group|
Current Fields of Interest: Medicinal/Synthetic Bioorganic/Organic Chemistry and Drug Design: Discovery, design and synthesis of nucleoside/nucleotide and heterocyclic enzyme inhibitors with chemotherapeutic emphasis in the areas of anticancer, antiviral, antibiotic, antifungal and antiparasitic targets. Goals include development of potent inhibitors to shut down disease replication pathways through a combination of cross-disciplinary synthetic, biological screening, mechanistic, computational and structure-based drug design techniques.
The primary focus of the Seley-Radtke laboratories involves the design and synthesis of flexible nucleoside ('fleximers') and nucleobases ('flex-bases) inhibitors as a powerful technique to overcome the development of resistance to currently used therapeutics. This approach has caused a paradigm shift in the medicinal chemistry community due to the ability of the fleximers and flex-bases to retain full potency when faced with 'escape mutations' in biologically critical enzymatic systems. The inherent flexibility of the inhibitors allows them to conformationally adjust to steric and electronic clashes encountered in the binding site, and to engage secondary amino acids not previously involved in the enzyme's mechanism of action.
A second project involves the strategic use of prodrugs to increase oral bioavailability for a series of tricyclic nucleosides shown to be active against hepatitis C virus (HCV). This approach also allows the nucleosides to bypass the first rate-limiting kinase-mediated phosphorylation in the requisite intercellular conversion to their biologically active triphosphate form. Current efforts include applying this approach to other viruses such as the HIV and herpes viruses. A third project employs carbocyclic nucleoside inhibitors as potential antiparasitic drugs by inhibiting methylation of the 'cap four' structure of parasite mRNA required for proper transcription and translation. All of the projects being pursued in the Seley-Radtke laboratories employ structure activity relationship (SAR) algorithms for the biological enhancement of lead compounds.
A third project focuses on the use of nucleosides and nucleobases as anticancer agents. For example, the potent activity exhibited by gemcitabine, Ara-C and other related FDA-approved anticancer analogues, has led to numerous structural modifications designed to increase target specificity and potency. Following upon the recent observation that several nucleobase analogues including thiophene-expanded purines, as well as pyrrolo – and thienopyrimidines designed in our laboratories have exhibited potent and selective activity against several key cancers including lung, colon, leukemia, renal, and breast cancers (among others), we have initiated a program to elucidate their mechanism of action, as well as to further study their highly promising activity in vitro and in vivo.
Intimately related to the goals of the drug design projects, synthetic organic research focus includes the discovery of unique strategies to solve design challenges using state of the art 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. Cross-disciplinary chemical biology research involves use of enzymatic assays to survey the effectiveness of the potential drug candidates, as well as investigations into polymerase fidelity with modified nucleotide analogues that possess unique structural advantages for enhanced recognition.