Biopharmaceutical drugs that are responsive to a physiological change or to an external signal offer the prospect of precise control of their function, but have remained elusive. We have pursued the control of properties of peptides and proteins by chemical modification that incorporate metal ion binding ligands and reactive linkers.
Metal ion-induced self-assembly (SA) of proteins into higher-order structures can provide dynamic nano-assemblies. Studies on human insulin (HI) analogs modified with the tridentate chelator terpyridine (Tpy) plant-derived oligogalacturonan (OGA) carbohydrates are presented. SA of the insulin analog LysB29Tpy-HI in the presence of metal ions, such as Zn2+, Fe2+ and Eu3+ provided control of the overall size of the nano-assemblies and their fractal dimensionality. We then showed that metal ions can be used to directly control the pharmacokinetics of chemically modified insulins by SPECT/CT imaging of rodents.
Finally, a glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. We developed glucose cleavable linkers based on thiazolidine structures. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.