Discovery of Truncated Cyclic Peptides Targeting an Induced‐Fit Pocket on PCSK9

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low‐density lipoprotein cholesterol (LDL−C) levels by promoting hepatic LDL receptor (LDL−R) degradation. We previously identified and optimized 13‐mer cyclic peptides that bind to a novel, induced‐fit pocket adjacent to the binding interface of PCSK9 and LDL−R and effectively disrupted the PCSK9/LDL−R protein‐protein interaction (PPI) both in vitro and in vivo. However this series of large cyclic peptides required charged groups for function and lacked oral bioavailability in rodents. We describe herein multiple structure‐based modifications to these original peptides to yield truncated, neutral molecules with full PPI function in both biochemical and cellular assays. In parallel, new mRNA‐peptide display screens identified non‐functional 8‐ and 9‐mer compounds which ligand the induced‐fit pocket in a distinct manner. Taken together, these studies indicate multiple directions to reduce the size and complexity of this peptide class toward a true small molecule oral agent.