Speakers.
Herzon Seth, PhD
Yale University, New Haven
Topic: Synthetic studies of complex glycosylated natural products and strategies for the stereocontrolled synthesis of 2-deoxyglycosides
Abstract: 2-Deoxy-O-glycosides are abundant in bacterial secondary metabolites and are often a critical determinant of biological activity. However, the stereocontrolled synthesis of these glycoside linkages is notoriously difficult. Here I will describe synthetic studies of lomaiviticin A, a cytotoxic C2-symmetric metabolite that contains four 2,6-dideoxyglycosides, two of which are β-linked. Our studies of lomaiviticin A motivated us to explore the use of using 2,6-dideoxyglycosyl bromides are donors in a Koenigs−Knorr glycosylation, to access β-linked products. We show that with careful choice of glycoside protecting group, these donors provide high levels of β-selectivity for a range of acceptors. These studies also motivated the development of an Umpolung glycosylation that proceeds through a stereodefinied anomeric anion intermediate. This Umpolung approach provides either α- or β-linked 2-deox-O-glycosides from a single carbohydrate donor.
Carole Ann Bewley, Ph.D.
Lab of Bioorganic Chemistry, NIDDK, National Institutes of Health
Topic: Advancing carbohydrate-targeting proteins for antiviral and in vivo studies
Abstract: Glycans are ubiquitous in biology, as are the proteins, or lectins, that have evolved to recognize them with high specificity and affinity/avidity. Over the past two decades a handful of lectins have been studied intensely for their ability to potently block infection by enveloped viruses such as HIV and SARS-CoV-2. In addition to determining the structural and biophysical basis for carbohydrate recognition of lectins, we have been interested in harnessing their full potential as potent antivirals. Our recent efforts in this area will be presented, including the design of and rationale for engineering of antibody-lectin conjugates, their pharmacokinetic and immune effector function profiles, and in vivo activity in mouse models of viral infection. Our current gaps in knowledge and areas for future study will also be discussed.
Stacy A. Malaker, PhD
Yale University, New Haven
Topic: Mucinomics as the next frontier of mass spectrometry
Abstract: Mucin-domain glycoproteins are densely O-glycosylated and play key roles in a host of biological functions. However, their dense O-glycosylation remains enigmatic both in glycoproteomic landscape and structural dynamics, primarily due to the challenges associated with studying mucin domains. Here, we present advances in the mass spectrometric analysis of mucins, including the characterization of mucinases, enrichment techniques, and complete mucinomic mapping of translationally relevant mucin proteins.
Christopher Reid, PhD
Bryant University, Rhode Island
Topic: Breaking down the wall: Chemical biology tools to study the microbial cell wall and the search for new antibiotics
Abstract: Antimicrobial resistance is one of the top global public health threats and is estimated to be directly responsible for 1.3 million global deaths per year with a projected healthcare cost of up to $1 trillion USD by 2050. The cell wall of bacteria has provided a treasure trove of clinically relevant antimicrobial targets. While our understanding of the biosynthesis of cell wall polysaccharides is well established, our knowledge of the degradative and remodeling processes and their coordination with biosynthesis lags behind. To address this gap in understanding we have developed several glycoconjugates and peptidomimetics that target carbohydrate acting enzymes in bacteria. This talk will discuss a longstanding project in the lab, the characterization of N-acetylglucosaminidases associated with peptidoglycan degradation and the use of diamides and glycosyl triazole inhibitors to investigate the role these enzymes play in peptidoglycan metabolism of Gram-positive bacteria.
Linda C. Hsieh-Wilson , PhD
California Institute of Technology, Pasadena, CA
Topic: Glycan Synthesis, Recognition and Roles in Neuroplasticity
Abstract: The field of chemical neurobiology is providing insights into the molecules and interactions involved in neuronal development, sensory perception, and memory. This seminar will describe our efforts to understand the structure-function relationships of glycosaminoglycans (GAGs) and how GAGs contribute to neuroplasticity – the ability of the brain to adapt and form new neural connections. Using a combination of synthetic chemistry, biochemistry, computational chemistry, cell biology, and neurobiology, we have developed a diverse set of chemical tools for studying the biology of GAGs. I will discuss how the synthesis of large GAG libraries provides insights into their elusive ‘sulfation code’ and reveals interesting parallels to DNA recognition. Our studies also indicate that particular sulfation motifs on GAGs regulate signaling that underlies neuronal processes such as axon regeneration, synaptic plasticity, and social memory. The ability to identify and modulate these sulfation motifs opens up new opportunities for neuronal regeneration and repair after stroke, central nervous system injury, and neurodegenerative diseases.