Design of organo-peptides as bipartite PCSK9 antagonists.

Proprotein convertase subtilisin/kexin 9 (PCSK9) has become an important therapeutic target for lipid lowering, since it regulates LDL-c levels by binding to liver LDL receptors (LDLR) and effecting their intracellular degradation. However, the development of small molecule inhibitors is hampered by the lack of attractive PCSK9 target sites. We recently discovered a cryptic groove that is situated adjacent to the main LDLR binding site and is accessible to compounds. Here, we designed potent bipartite inhibitors by appending organic moieties to a helical groove-binding core peptide to reach a hydrophobic pocket in the proximal LDLR binding region. The ultimately designed 1-amino-4-phenylcyclohexane-1-carboxamido extension improved the core peptide affinity by >100-fold, yielding organo-peptide antagonists that potently inhibited PCSK9 binding to LDLR and preserved cellular LDLR. These new bipartite antagonists have reduced mass and improved potency compared to the first-generation peptide antagonists, further validating the PCSK9 groove as viable therapeutic target site.