Our laboratory will interrogate and/or block function in biological systems with functionalized polymers based on
recent developments from our laboratory that provide insights into how to control binding and activation of
receptors, and into control of ruthenium-catalyzed metathesis copolymerizations. First, cholera is still a life-
threatening illness with an annual incidence of ~2.9 million cases and ~95,000 deaths annually in endemic
countries. Many outbreaks of cholera would be staunched by a therapeutic that reduced cell binding and thus
spreading of V. cholerae, the etiologic agent. Our laboratory and collaborators demonstrated that cholera toxin
B pentamer (CTB) and a norbornyl polymer randomly displaying galactose and fucose self-assemble into cross-
linked CTBn–glycopolymer networks. Larger aggregates result in better inhibition of cholera intoxication.
Synthesis of different fucose/galactose polymer systems, analysis of the dependence of aggregation capture
and kinetics on polymer structure, in combination with toxicity testing will be undertaken to develop simple, oral
therapeutics for cholera disease. Second, about 12% of American males between the ages of 15-44 are infertile
or subfertile, and failure of sperm to undergo acrosomal exocytosis (AE) is responsible for a significant fraction.
Better molecular diagnostics are required to diagnose subfertility. We demonstrated that human and mouse
sperm acrosomal exocytosis (AE) are activated with glycopolymers, although highly cooperative inhibition of AE
is observed at higher concentrations of the dose-response curve. Polymers with different backbones, sugar
densities, and sugars will be utilized to reduce cooperativity in the inhibition arm and to analyze which are best
for activation of human AE. The most effective probes will be used to identify the human AE sperm receptor.
Third, copolymers with well-controlled microstructure display superior morphology and enhanced properties,
such as spatial organization, folding and self-assembly. We demonstrated that precisely alternating AB
copolymers can be prepared from bicyclo[4.2.0]oct-6-ene-7-carboxamides (A) and large unstrained
cycloalkenes (B) with Grubbs III catalyst through alternating ring-opening metathesis polymerization. The A
monomer substituent and the microsequence of the polymer define surface behavior and solution structure
morphologies. Mechanistic structure-activity studies with A monomer varying C7 substituents (ketone, ester,
methenyl) will be undertaken to understand the source of alternating selectivity with an expanded B monomer
repertoire. These SAR studies will allow further exploitation of AROMP for gradient copolymer synthesis to tune
material properties and functions in one-pot polymerization reactions. The underlying chemical synthetic
methodologies proposed for these three discrete projects are highly related through polymer synthesis. We
anticipate synergy and support between project researchers will provide further opportunities for innovation that
cross between projects.