Abstract
The synthesis and full NMR and MS characterization of novel linear and macrocyclic polymeric scaffolds for sulfated polysaccharide presentation has been performed for this project. Coupling of the synthesized polymeric scaffolds to sulfated glycodendrons affords sulfated glycopolymers with significant potential as HSPG (heparan sulfate proteoglycan) mimics. Numerous viruses including HIV, SARS-CoV-2 and HPV use cellular HSPGs as co-receptors in the infection cycle. Dendrimers with sulfated sugars as surface groups have been used as HSPG mimics due to high multivalent carbohydrate-protein binding potential between numerous surface groups and polybasic regions in viral surface proteins. HSPG mimics target an entire group of pathogens and thus have significant potential as preventative broad-spectrum antiviral therapeutics. For this project, new linear and macrocyclic polymeric architectures were created to increase glycopolymer surface area, multivalency, and flexibility over previous spherical PAMAM (polyamidoamine) dendrimers. Molecular dynamics (MD) simulations performed by the Kràl Lab (University of Illinois- Chicago) showed significant interactions between simulated linear and macrocylic glycopolymers and the HIV spike protein gp120 and the S spike protein for SARS-CoV-2, guiding the synthetic project. The linear and macrocyclic polymeric cores were synthesized in 18 and 20 steps, respectively, in a divergent pathway heavily relying on click chemistry and symmetry. The structures have a poly(amidoether)) backbone with all carbons derived from four starting materials (hexa-ethylene glycol, ethanolamine, propargyl bromide, and 1,3-diaminopropane). The synthetic pathway may be easily modified to increase glycodendron attachment points on the polymer, allowing scaffolds to be redesigned and tuned for increased binding potential to target viral proteins.
Both the linear and macrocyclic structures will ultimately be coupled to sulfated glycodendrons and evaluated for binding to gp120 and S through ELISA (Enzyme-linked Immunosorbent Assay) and MST (MicroScale Thermophoresis) experiments, before inhibition of infectivity assays and cytotoxicity analysis. Biological assay results will show the effectiveness of these unique glycopolymer architectures and dictate the future approach in developing new glycopolymers as broad-spectrum therapeutics.