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

2024 WARF Therapeutics Distinguished Lecture in Drug Discovery

• Jeffrey Aubé, PhD
• University of North Carolina

New Approaches to Tuberculosis Therapeutics

Tuberculosis (TB) continues to be a major worldwide health problem, despite the existence of numerous drugs for its treatment. This is in part due to the long therapeutics times required to administer cocktails of front-line therapeutics and in part due to the emergence of even more challenging long-term strains. For these reasons, new therapeutic agents for the treatment of TB continue to be sought. In collaborative work with the laboratory of Carl Nathan (Weill–Cornell Medicine) and others, we have sought to find new chemotypes as potential anti-TB agents and to identify new biochemical targets for drug treatment. In this talk, I will describe our efforts in this area, beginning with early approaches to explore beta-lactam antibiotics as possible TB agents. More recent efforts have been focused on finding inhibitors of phosphopantetheinyl transferase (PptT). PptT carries out central biochemistry that is essential for mycobacterial survival; for this reason, it has been a long sought-target for antibacterial agent development. This story begins with our team’s discovery of the first effective small-molecule inhibitors of PptT, efforts to use bioisostere design to create a new series, and more recent chemotypes of PptT.

Hosted by Jennifer Golden

Jeffrey Aubé, PhD
Esehlman Distinguished Professor
Division of Chemical Biology & Medicinal Chemistry
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill

Jeffrey Aubé attended the University of Miami, where he did undergraduate research with Professor Robert Gawley. He received his Ph.D. in chemistry in 1984 from Duke University, working with Professor Steven Baldwin, and was an NIH postdoctoral fellow at Yale University with Professor Samuel Danishefsky. From 1986 until 2015,he held a faculty position in the Department of Medicinal Chemistry at the University of Kansas. In 2015, he moved to the University of North Carolina, where he is an Eshelman Distinguished Professor in the Division of Chemical Biology and Medicinal Chemistry and holds a joint appointment in the Department of Chemistry.