Researchers designed a new class of small cyclic peptides that block PCSK9 and could potentially become oral, once-daily cholesterol-lowering drugs.
Oral once-daily targetCurrent PCSK9 inhibitors require injection every 2-4 weeks. These optimized bicyclic peptides are designed to work as daily oral pills.
What the researchers found
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.
Why it matters
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.
How the study worked
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).
Who was studied
In vitro cell assays and animal models (mice, rats, cynomolgus monkeys)
What this study cannot tell us
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.
How to read the evidence
This is preliminary-grade evidence focused on drug discovery and chemical optimization. While the compounds show promise in laboratory and animal testing, no human clinical data exist. The path from optimized lead compound to approved drug typically takes many years.
When this study was published
Published in 2020. These compounds may have progressed further in development since publication; check for follow-up studies or clinical trial registrations.
The bigger picture
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).
Questions still open
- Can these bicyclic peptides achieve sufficient oral bioavailability in humans to lower LDL cholesterol meaningfully?
- How will these peptide PCSK9 inhibitors compare in cost and accessibility to existing antibody-based PCSK9 drugs?
- What safety profile will emerge as these compounds move through preclinical and clinical development?
Common questions
What is PCSK9 and why is blocking it important?
Why would an oral PCSK9 inhibitor be a big deal?
Read the original research
Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design.
Journal of medicinal chemistry, 63(22), 13796-13824
Citation
Alleyne, Candice; Amin, Rupesh P; Bhatt, Bhavana; Bianchi, Elisabetta; Blain, J Craig; Boyer, Nicolas; Branca, Danila; Embrey, Mark W; Ha, Sookhee N; Jette, Kelli; Johns, Douglas G; Kerekes, Angela D; Koeplinger, Kenneth A; LaPlaca, Derek; Li, Nianyu; Murphy, Beth; Orth, Peter; Ricardo, Alonso; Salowe, Scott; Seyb, Kathleen; Shahripour, Aurash; Stringer, Joseph R; Sun, Yili; Tracy, Rodger; Wu, Chengwei; Xiong, Yusheng; Youm, Hyewon; Zokian, Hratch J; Tucker, Thomas J. (2020). Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design.. Journal of medicinal chemistry, 63(22), 13796-13824. https://doi.org/10.1021/acs.jmedchem.0c01084