Researchers successfully truncated large cyclic peptides that block PCSK9 — a key driver of high cholesterol — into smaller, neutral molecules that retain full activity and move closer to becoming oral drugs.
13-mer → smaller neutral peptidesLarge charged cyclic peptides were systematically truncated into smaller, neutral molecules that retained full ability to block PCSK9 from degrading LDL receptors.
What the researchers found
Starting from previously identified 13-amino acid cyclic peptides, the researchers used structure-based design to create truncated, electrically neutral versions that maintained full ability to disrupt the PCSK9/LDL-receptor protein-protein interaction in both biochemical and cellular assays.
The original larger peptides required charged chemical groups to function and lacked oral bioavailability in rodents — a major barrier to pill development. The new truncated versions eliminated this charge requirement.
In parallel, mRNA-peptide display screening identified novel 8- and 9-amino acid compounds that bind the same induced-fit pocket on PCSK9 but in a structurally distinct manner. Although these shorter peptides were not functionally active on their own, they demonstrate that smaller molecules can access this binding site, providing additional starting points for further optimization toward true small-molecule oral agents.
Why it matters
Current PCSK9 inhibitors (evolocumab, alirocumab) are injectable antibodies that dramatically lower cholesterol but require regular injections. An oral PCSK9 inhibitor would be transformative for the millions of patients who need cholesterol lowering but prefer pills over injections. This work demonstrates a viable path from peptide hits to smaller, oral-compatible molecules targeting a pocket on PCSK9 that was previously unknown.
How the study worked
The team used structure-based drug design to systematically modify their original 13-mer cyclic peptides, reducing size and removing charged groups while monitoring activity. Peptide variants were tested in biochemical assays measuring PCSK9/LDL-receptor binding disruption and in cellular assays. In parallel, mRNA-peptide display — a technique that screens billions of peptide sequences simultaneously — was used to discover new short peptides that bind the PCSK9 induced-fit pocket. Structural analysis was used to understand how different peptide classes interact with the target.
What this study cannot tell us
The truncated peptides have not been tested for oral bioavailability — the key practical goal. The shorter 8-9 mer peptides identified by display screening were not functionally active, meaning further optimization is needed. No in vivo efficacy or pharmacokinetic data are reported for the new truncated compounds. The induced-fit pocket may behave differently across PCSK9 variants in diverse patient populations.
How to read the evidence
This is a preclinical drug discovery study demonstrating in vitro and cell-based activity of novel compounds. While the biochemical findings are robust, no animal efficacy or pharmacokinetic data for the new compounds are presented, and clinical relevance remains to be established through further development.
When this study was published
Published in 2024, this is a recent contribution to the active field of oral PCSK9 inhibitor development. Several competing programs are in various stages of clinical development, so the landscape may evolve quickly.
The bigger picture
The quest for an oral PCSK9 inhibitor is one of the most competitive areas in cardiovascular drug development. Most approaches have struggled because PCSK9's interaction with LDL receptors involves a large, flat protein surface that's hard for small molecules to disrupt. This team's discovery of an induced-fit pocket — a hidden binding site that only appears when a peptide binds — provides a unique druggable target. Successfully shrinking peptides while maintaining activity is a critical step in the peptide-to-small-molecule transition that could reshape cholesterol treatment.
Questions still open
- Can the truncated neutral cyclic peptides achieve oral bioavailability in animal models, overcoming the limitation of the original series?
- Could the non-functional 8-9 mer peptides be optimized to gain activity while maintaining their smaller size advantage?
- How does the induced-fit pocket on PCSK9 compare to binding sites targeted by other oral PCSK9 inhibitor programs in development?
Common questions
What is PCSK9 and why do we want to block it?
Why is making an oral PCSK9 inhibitor so difficult?
Read the original research
Discovery of Truncated Cyclic Peptides Targeting an Induced-Fit Pocket on PCSK9.
ChemMedChem, 19(23), e202400208
Citation
Grosche, Philipp; Flyer, Alec N; Gattlen, Raphael; Xu, Mei; Golosov, Andrei A; Vera, Victoria; Pickett, Stephanie; Brousseau, Margaret E; Chopra, Rajiv; Clairmont, Kevin B; Koch, Alexander; Liu, Eugene; Reid, Patrick; Perry, Lauren; Yang, Lihua; Yang, Qing; Monovich, Lauren G. (2024). Discovery of Truncated Cyclic Peptides Targeting an Induced-Fit Pocket on PCSK9.. ChemMedChem, 19(23), e202400208. https://doi.org/10.1002/cmdc.202400208