New Cyclic Peptides Could Become the First Oral PCSK9 Cholesterol Drugs

Researchers used mRNA display screening to discover a new series of cyclic peptides that block the interaction between PCSK9 and the LDL receptor — the same target hit by existing injectable antibody drugs like evolocumab and alirocumab. Through structure-based drug design, they optimized these peptides into smaller, more metabolically stable bicyclic compounds (such as compound 78) that could potentially be developed into oral, once-daily PCSK9 inhibitors for lowering cholesterol.

The team used mRNA display — a technique where trillions of peptide sequences are screened simultaneously — to identify initial hit compounds that block the PCSK9/LDLR protein-protein interaction. They then used X-ray crystallography and structure-activity relationship studies to systematically optimize these peptides, reducing molecular weight and improving metabolic stability while maintaining potency. Testing included cell-based assays and animal models (mice, rats, and cynomolgus monkeys).

Current PCSK9 inhibitors are highly effective at lowering LDL cholesterol but require injection every 2-4 weeks, which limits their adoption. An oral peptide PCSK9 inhibitor taken once daily could dramatically expand access to this class of cardiovascular drugs, making potent cholesterol-lowering therapy as simple as taking a pill.

This work sits at the intersection of two major pharmaceutical trends: the push to make injectable biologics available as oral drugs, and the use of cyclic peptides as a drug class that combines the potency of large molecules with the oral bioavailability of small molecules. If successful, oral PCSK9 peptide inhibitors could join the growing list of peptide drugs transitioning from injection to pill form, similar to what happened with oral semaglutide (Rybelsus).

This is a drug discovery paper focused on chemical optimization — no human efficacy or safety data exist for these compounds. The transition from potent lab compounds to successful oral drugs faces many hurdles including bioavailability, manufacturing, and clinical trial outcomes. Specific in vivo efficacy data for the lead compounds are limited in the abstract.