Biomolecular inhibitors of protein-protein interactions typically have low therapeutic potential because of their poor in vivo half-lives. Half-life extension by binding to the serum protein albumin has emerged as a promising drug design strategy, but its application to inhibitors of proprotein convertase subtilisin-like/kexin type 9 (PCSK9), a clinical validated protein target for treating cardiovascular disease, has yet to be explored.
In this poster, I will describe the design, structural and biophysical characterization of peptidic inhibitors that prevent PCSK9 binding to the EGFA structural domain of the LDL cholesterol receptor while also being able to bind to serum albumin. The affinities of designed peptides were tested by biophysical (e.g. surface plasmon resonance and fluorescence polarization) experiments. Structural characterization was performed by NMR, CD spectroscopy and computational modelling.
My results showed that one of the designed peptides, YZ008, could bind to PCSK9 with high affinity (31.8 ± 1.65 nM) and human serum albumin (~4 uM). Structural characterization showed the peptide adopts a helical structure and its ability to bind albumin does not hinder its function as a PCSK9 inhibitor.
In conclusion, we have demonstrated the utility of a half-life extension strategy for the optimization of a PCSK9 inhibitor for treating hypercholesterolemia. This strategy has broad applications for therapeutic improvement of biomolecular drug candidates.