Ultrapotent Cyclic Peptide in Cyclotide Scaffold Blocks Blood Clotting Factor XIIa
A selective cyclic peptide inhibitor of β-Factor XIIa was engineered within a cyclotide scaffold, combining ultrapotent anti-clotting activity with the exceptional stability of plant-derived cyclotide structures.
Quick Facts
What This Study Found
Engineered cyclotide containing a Factor XIIa inhibitor loop achieved ultrapotent and selective inhibition of human β-Factor XIIa while maintaining the cyclotide scaffold's proteolytic stability and cell permeability.
Key Numbers
>10^12 library; pM Ki for FXIIa; >1,000-fold selectivity; MCoTI-II scaffold; co-crystal structure
How They Did This
Peptide engineering study. Factor XIIa inhibitor sequence grafted into cyclotide scaffold. Potency and selectivity profiling against coagulation factors. Stability and cell permeability assessment.
Why This Research Matters
Factor XII drives pathological blood clotting (thrombosis) without being needed for normal wound healing — making it an ideal anticoagulant target. A cyclotide-based inhibitor could be more stable than existing peptide anticoagulants.
The Bigger Picture
Cyclotides as drug scaffolds represent one of the most exciting developments in peptide therapeutics. Their inherent stability solves the major weakness of peptide drugs (rapid degradation), and their engineerability allows insertion of diverse bioactive sequences.
What This Study Doesn't Tell Us
In vitro potency and selectivity study. In vivo anti-thrombotic efficacy not tested. Cyclotide manufacturing at pharmaceutical scale is challenging. Immunogenicity of plant-derived scaffold in humans unknown.
Questions This Raises
- ?Would this cyclotide prevent thrombosis in vivo without bleeding risk?
- ?Can cyclotide scaffolds deliver other anti-clotting or anti-inflammatory peptides?
- ?Would oral delivery of cyclotide anticoagulants be possible given their stability?
Trust & Context
- Key Stat:
- Ultrapotent + ultrastable Cyclotide scaffold provides exceptional protease resistance and cell permeability while the engineered inhibitor loop delivers ultrapotent Factor XIIa selectivity
- Evidence Grade:
- Low-to-moderate evidence: thorough in vitro characterization with potency and selectivity data, but no in vivo anticoagulant testing.
- Study Age:
- Published 2021. Cyclotide-based drug design is advancing with multiple therapeutic applications in development.
- Original Title:
- An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human β-Factor XIIa in a Cyclotide Scaffold.
- Published In:
- Journal of the American Chemical Society, 143(44), 18481-18489 (2021)
- Authors:
- Liu, Wenyu, de Veer, Simon J, Huang, Yen-Hua, Sengoku, Toru, Okada, Chikako, Ogata, Kazuhiro, Zdenek, Christina N, Fry, Bryan G, Swedberg, Joakim E, Passioura, Toby, Craik, David J, Suga, Hiroaki
- Database ID:
- RPEP-05562
Evidence Hierarchy
Frequently Asked Questions
What is a cyclotide?
A cyclotide is a plant-derived peptide with a circular backbone and a "cystine knot" of disulfide bonds. This unique structure makes it incredibly stable — resisting digestive enzymes, heat, and degradation. Scientists can engineer new functions into the cyclotide by inserting bioactive sequences.
Why target Factor XIIa for anticoagulation?
Factor XII drives pathological blood clot formation (thrombosis, strokes, heart attacks) but is NOT required for normal wound healing. Blocking it should prevent dangerous clots without increasing bleeding risk — the holy grail of anticoagulation therapy.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-05562APA
Liu, Wenyu; de Veer, Simon J; Huang, Yen-Hua; Sengoku, Toru; Okada, Chikako; Ogata, Kazuhiro; Zdenek, Christina N; Fry, Bryan G; Swedberg, Joakim E; Passioura, Toby; Craik, David J; Suga, Hiroaki. (2021). An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human β-Factor XIIa in a Cyclotide Scaffold.. Journal of the American Chemical Society, 143(44), 18481-18489. https://doi.org/10.1021/jacs.1c07574
MLA
Liu, Wenyu, et al. "An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human β-Factor XIIa in a Cyclotide Scaffold.." Journal of the American Chemical Society, 2021. https://doi.org/10.1021/jacs.1c07574
RethinkPeptides
RethinkPeptides Research Database. "An Ultrapotent and Selective Cyclic Peptide Inhibitor of Hum..." RPEP-05562. Retrieved from https://rethinkpeptides.com/research/liu-2021-an-ultrapotent-and-selective
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.