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

Pharmaceutical Sciences Seminar Series

(Drug ACTION Specific Seminar)

• Nan Gao, PhD
• Rutgers University

Non-canonical Paneth cell functions regulate intestinal inflammatory response

Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. I will show experiments that demonstrate the impact of lack or ectopic lysozyme production on colonic inflammation. I will also show data about how Lyz1-deficiency modulates the gut bacterial composition and intestinal immune responses to bacterial molecular patterns. I will present biochemical and immunology evidence to suggest that Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses.

In addition, I will shed light on our recent finding that a direct engagement of intestinal lysozyme with enteric pathogens such as Salmonella promotes the release of bacterial virulence factors that are barrier-impairing and pro-inflammatory.

In the end I’ll discuss our ongoing work investigating the Paneth cell subsets that may be important for host responses to infection and inflammation.

Hosted by Ting Fu