Stereocontrolled polymerizations can be used to generate isomers of synthetic polymers with divergent physical properties. These differences are derived from changes in morphology, which biopolymers, like proteins, are particularly sensitive towards. It is hypothesized that the therapeutic output of proteomimetic polynorbornene peptide-bottlebrushes containing olefins along their backbone will display similar sensitivity to changes in alkene orientation. Herein, we employ a cis-selective Ruthenium initiator for Ring-Opening Metathesis Polymerization (ROMP) of nornbornenyl-peptide monomers to generate peptide brush polymers displaying a variety of therapeutic sequences. The structure and function of these cis-enriched polynorborenenes are compared to polymers containing a nearly equal mix of cis and trans olefins as generated by the third-generation Grubbs’ initiator. In one example, cis-polymers displaying an anti-angiogenic, CD36 binding peptide designed to mimic the action of thrombospondin-1 (cis-poly(ABT898)), outperformed the equivalent, isomerically mixed polymers at inhibiting the uptake of fatty acids by CD36. In addition, the cytotoxicity of cis-poly(ABT898) was greatly reduced in retinal epithelial cells, making them an attractive target for the treatment of age-related macular degeneration. Preliminary small-angle X-ray scattering experiments suggest that polymers containing multiple trans-alkenes tend to be globular, while highly cis-enriched polymers elongate which may promote multivalent behavior. To generalize these results, additional cell-surface and intracellular peptide targets are being investigated, including natural hormones, and peptides targeting intracellular, disease driving protein-protein interactions. Identifying key differences in the bioactivity for each of these systems is motivated by a consideration of the desired morphology for macromolecular drugs in the same way that bond orientation is precisely controlled for small molecule drugs.

Effects of backbone alkene stereochemistry on the bioactivity of peptide-modified polynorbornene brush polymers

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