A High Throughput Approach for Designing Polymers That Mimic the TRAIL Protein

We have leveraged a high throughput approach to design a fully synthetic polymer mimic of the chemotherapeutic protein "TRAIL". Our design enables the synthesis of libraries of star-shaped polymers presenting exactly one receptor binding peptide at the end of each arm with no purification steps. Clear structure-activity relationships in screening for receptor binding and the apoptotic activity on colon cancer lines (COLO205) led us to identify trivalent structures, ∼1.5 nm in hydrodynamic radius as the best mimics. These showed IC₅₀ values ∼2 μM and resulted in the elevated levels of caspase-8 expected from this mechanism of cell death. Our results demonstrate the potential for HTP screening methods to be used in the design of polymers that can mimic a whole range of complex therapeutic proteins.