Date of Award
1-1-2025
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Vitor Pomin
Second Advisor
Marc Slattery
Third Advisor
Paul Boudreau
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Glycosaminoglycans (GAGs) are heteropolysaccharides widely exploited in the clinic and as molecular models in biomedical research. Marine-derived GAG analogs, particularly sulfated fucans and fucosylated chondroitin sulfates exhibit unique and diverse glycan motifs that are not found in the typical mammalian GAGs. The distinctive structures of the marine sulfated glycans (MSGs) not only expand the structural landscape of GAG-like molecules but also provide valuable platforms to elucidate structure-activity relationships and explore their potential as novel scaffolds for glycan-based therapeutic development. This dissertation presents the isolation, structural characterization, controlled depolymerization, and functional evaluation of several MSGs, highlighting their therapeutic potential, particularly those derived from sea cucumbers. An integrated analytical platform, comprising nuclear magnetic resonance spectroscopy, liquid chromatography, mass spectrometry, electrophoresis, and both chemical and enzymatic degradation, was employed to characterize their structures at both their polymeric and oligomeric levels. Their biomedical potential was subsequently assessed using a series of in vitro assays, including anticoagulant testing with human plasma and purified coagulation factors. In response to the coronavirus disease 2019 (COVID-19) pandemic, the antiviral potential of MSGs was also investigated. Several MSGs were tested for their ability to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus entry by disrupting interactions between the viral spike protein and host cell surface heparan sulfate proteoglycans. The results demonstrated potent inhibition against both the wild-type and Delta variants, underscoring the potential of marine glycans as broad-spectrum antiviral agents. Another focus of this work was the evaluation of these glycans as inhibitors of heparan-6-O-endosulfatase 2 (Sulf-2), a human extracellular endosulfatase implicated in cancer progression. Enzyme activity assays using fluorogenic and chromatographic substrates revealed that specific MSG can inhibit Sulf-2 activity. Specific structural features, such as fucosylation patterns, sulfation positions, and backbone composition, were found to influence the observed biological activities. Altogether, the findings presented here highlight structurally distinct MSGs as promising multifunctional molecules with anticoagulant, anticancer, and antiviral properties. These results support the continued development of MSGs as lead compounds in glycan-based drug discovery.
Recommended Citation
Farrag, Marwa, "Structure and Function of Sulfated Fucans and Fucosylated Chondroitin Sulfates: Therapeutic and Mechanistic Insights" (2025). Electronic Theses and Dissertations. 3274.
https://egrove.olemiss.edu/etd/3274