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 antiviral, anticancer, antibiotic, and antiparasitic targets. Primary goals include development of potent inhibitors to shut down disease replication pathways through a combination of cross-disciplinary synthetic, biological screening, mechanistic, and structure-based drug design techniques.
The primary focus for the Seley-Radtke laboratories involves the design and synthesis of flexible nucleoside (“fleximers”) and nucleobases (“flex-bases) inhibitors as a powerful approach to overcome the development of resistance to currently used therapeutics. The fleximers and flex-bases are able 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. Potent activity has been uncovered with a series of “doubly flexible” acyclic nucleosides and their corresponding prodrugs against various viruses including coronaviruses such as SARS and MERS-CoV. This is particularly notable since to date, no cure has been approved and prior to our discovery, no nucleoside had successfully inhibited coronaviruses. Other targets under investigation with these structurally unique analogues include Ebola and Marburg by inhibition of viral polymerases with fleximers and their corresponding prodrugs. The prodrugs allow the nucleosides to bypass the first rate-limiting kinase-mediated phosphorylation in the requisite intercellular conversion to their biologically active triphosphate form. Other viral targets currently under investigation for the fleximers include Zika, Dengue and Yellow Fever, among other high priority neglected diseases.
Related to the above projects, the use of flex-nucleobases to inhibit the protein-protein interactions (PPIs) for the HIV nucleocapsid NCp7 is also being pursued. NCp7 is of high interest due to its multifunctional role in HIV replication. We have published extensively on a series of non-nucleoside HIV inhibitors (NNRTIs) containing nucleobases that have also shown dual activity against tuberculosis and influenza.
In addition to viral targets, another project focuses on the use of 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 selective and highly potent (sub-nanomolar) levels of activity against several key cancers including lung, colon, leukemia, renal, and triple negative 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. These compounds have advanced to animal studies and as well as investigations to elucidate their mechanism of action.
All of the projects being pursued in the Seley-Radtke laboratories employ structure activity relationship (SAR) algorithms for the biological enhancement of lead compounds. 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 for the construction of modified heterocycles, carbohydrates and carbocyclic moieties. In addition, a cross-disciplinary chemical biology approach employs enzymatic assays to survey the effectiveness of the potential drug candidates, as well as to investigate polymerase fidelity with modified nucleotide analogues that possess unique structural advantages for enhanced molecular recognition.