Cholera has a global burden of approximately 1.4 to 4.3 million cases per year with a 2-3% mortality rate. Currently available vaccines provide limited protection with a ~65% efficacy rate over 5 years, and lower protection rates in children under 5 years of age. Cholera toxin engages sugar ligands on epithelial cells as a prelude to intoxication. About 11 % of American males between the ages of 15-44 are infertile or subfertile. Half of male fertility cases are clinically idiopathic or unexplained, however, systematic review suggests that over half of these cases are due to acrosomal failures. Engagement of sugar ligands by sperm receptor(s) activates sperm acrosomal exocytosis in sperm, which is essential for fertilization of the egg to occur. In both systems, the weak affinities of receptor and sugar ligand are converted into high avidity interactions through multivalent engagement. Polymeric probes provide a versatile strategy to investigate and control these types of multivalent ligand- receptor interactions. Polymerization chemistry lends itself to rapid assembly of repeating ligand units in a single synthetic step. However, most polymerization strategies provide narrow limits on the spacing and positioning of ligands that can be achieved. Thus, interpreting structure-activity relationships for polymers in cellular systems is a challenge that hinders translation into therapeutic or diagnostic applications. Our innovative approach is application of alternating copolymerization strategies developed in the Sampson laboratory. Our recent discovery of the bicyclo[4.2.0]oct-1(8)-ene-8-carboxamide/cyclohexene system for ring- opening metathesis allows the preparation of very long, alternating polymers with high monomer economy. The chemistry lends itself to controlling sequence beyond alternation. Using our polymer chemistry, we will (1) define the spacing and accessibility requirements for in vitro and in vivo inhibition of cholera intoxication; (2) identify the most physiologically relevant glyco-copolymer activators of mouse sperm acrosomal exocytosis; and (3) screen sperm from fertile and subfertile human males for glycopolymer-induced acrosomal exocytosis to define the structure-activity relationships that differentiate them. The proposed polymers in combination with their structural and functional characterization provide entry to possible therapeutics of cholera and diagnostics of male infertility and/or methods of male contraception.
We will use innovative polymerization chemistry to precisely position and space sugars in sequence- specific patterns. These studies will identify polymer structures that improve human health through prevention of acute intestinal disease, improvement of assisted reproductive technology outcomes, and improved fertility control methods.
|Li, Guofang; Sampson, Nicole S (2018) Alternating Ring-Opening Metathesis Polymerization (AROMP) of Hydrophobic and Hydrophilic Monomers Provides Oligomers with Side-Chain Sequence Control. Macromolecules 51:3932-3940|
|Wands, Amberlyn M; Cervin, Jakob; Huang, He et al. (2018) Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells. ACS Infect Dis 4:758-770|
|Chen, Lei; Li, Liqiang; Sampson, Nicole S (2018) Access to Bicyclo[4.2.0]octene Monomers To Explore the Scope of Alternating Ring-Opening Metathesis Polymerization. J Org Chem 83:2892-2897|
|Huang, He; Rodolis, Maria T; Bhatia, Surita R et al. (2017) Sugars Require Rigid Multivalent Displays for Activation of Mouse Sperm Acrosomal Exocytosis. Biochemistry 56:2779-2786|
|Rodolis, Maria T; Huang, He; Sampson, Nicole S (2016) Glycopolymer induction of mouse sperm acrosomal exocytosis shows highly cooperative self-antagonism. Biochem Biophys Res Commun 474:435-440|
|Parker, Kathlyn A; Sampson, Nicole S (2016) Precision Synthesis of Alternating Copolymers via Ring-Opening Polymerization of 1-Substituted Cyclobutenes. Acc Chem Res 49:408-17|
|Lee, Siyeon; Wang, Wei; Lee, Younjoo et al. (2015) Cyclic acetals as cleavable linkers for affinity capture. Org Biomol Chem 13:8445-52|
|Tan, Li; Li, Guofang; Parker, Kathlyn A et al. (2015) Ru-Catalyzed Isomerization Provides Access to Alternating Copolymers via Ring-Opening Metathesis Polymerization. Macromolecules 48:4793-4800|
|Wu, Linghui; Sampson, Nicole S (2014) Fucose, mannose, and ?-N-acetylglucosamine glycopolymers initiate the mouse sperm acrosome reaction through convergent signaling pathways. ACS Chem Biol 9:468-75|
|Tan, Li; Parker, Kathlyn A; Sampson, Nicole S (2014) A Bicyclo[4.2.0]octene-Derived Monomer Provides Completely Linear Alternating Copolymers via Alternating Ring-Opening Metathesis Polymerization (AROMP). Macromolecules 47:6572-6579|
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