Events

Pharmaceutical Sciences Seminar Series

(Drug DISCOVERY Specific Seminar)

• Kathie Seley-Radtke, PhD
• University of Maryland

Development of Pan-Viral Nucleoside Inhibitors

The severity and rapid spread of the coronavirus pandemic served to drive home that we were completely unprepared to fight such an outbreak. As a result, it became clear that there was a critical need for small molecule, orally bioavailable, broad-spectrum drugs that could be stockpiled and readily distributed when the next outbreak occurs. In that regard, for many years nucleos(t)ides have maintained a prominent role as one of the cornerstones of antiviral and anticancer therapeutics, and numerous scaffolds in nucleos(t)ide and nucleic acid drug design have been pursued. One such approach involves adding flexibility to the sugar moieties of nucleos(t)ides, for example, in the highly successful anti-HIV/HBV drug Tenofovir developed by Antonín Holý. In contrast, introduction of flexibility to the nucleobase scaffold has only more recently gained significance with the invention of our fleximers. This modification has led to a significant improvements in antiviral activity, and in some cases endowing the nucleoside with potent broad-spectrum activity across several viral families, when the parent rigid nucleoside was inactive. Another advantage observed is the ability to avoid resistance mechanisms related to point mutations by engaging secondary amino acid residues not previously involved in the mechanism of action. A second series of nucleosides being pursued in our group, involves insertion of a heterocyclic spacer ring in between the two moieties of the bicyclic purine ring system, forming an expanded tricyclic nucleoside with increased aromaticity. This modification has also led to potent antiviral activity, again targeting several different pathogens of pandemic concern. A brief history of their design, synthesis, and recent antiviral findings for these innovative nucleos(t)ide scaffolds will be discussed.

Hosted by Jennifer Golden