Cyclotides
Plant peptides with a head-to-tail cyclic backbone locked by a knotted disulfide core, so stable they survive boiling and gut proteases — used as scaffolds to make other peptides orally bioavailable rather than as drugs themselves.
Also known as cyclic cystine knot peptides, kalata B1, CCK peptides
In vitro only — Cell or tissue studies. A mechanism, not yet an effect in a living body.
Extensive structural, in-vitro and some rodent data validating the scaffold's stability and the feasibility of loop grafting. No cyclotide-based therapeutic has entered a registered human trial. Judge this as an enabling technology with a 20-year runway, not a compound.
How it works
Cyclotides were discovered when a Norwegian physician documented Congolese women brewing Oldenlandia affinis tea to accelerate labour; the uterotonic agent, kalata B1, turned out to survive boiling and oral ingestion intact. The scaffold consists of a continuous circular peptide backbone with six cysteines forming three disulfides, two of which plus their connecting backbone form a ring threaded by the third — the cystine knot. This gives thermal stability above 100 C and near-complete resistance to gut, serum and lysosomal proteases. Native cyclotides have insecticidal, antimicrobial, uterotonic and haemolytic activities, mostly mediated by binding phosphatidylethanolamine in membranes. The real interest is grafting: replacing a surface loop with a bioactive sequence transfers that activity onto a scaffold that is orally stable. Grafted cyclotides targeting VEGF-A, IL-2 receptor and myelin-specific T-cell responses in multiple sclerosis models have shown oral activity in animals, which is the property no ordinary peptide has.
Targets: Membrane phosphatidylethanolamine (native), Whatever target the grafted loop is designed against
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| No clinical protocol existsNot applicable. | — | not established | oral |
- · This is a scaffold technology, not a drug. There is no cyclotide dosing protocol because there is no cyclotide drug. Anything sold to consumers as 'cyclotides' is a plant extract of unknown composition.
Cycling
Not applicable.
Pharmacology
- Half-life
- Exceptionally long by peptide standards — grafted cyclotides have shown plasma half-lives of many hours to days in rodents, versus minutes for equivalent linear peptides.
- Onset
- Depends entirely on the grafted pharmacophore.
- Routes
- oral, subcutaneous, topical
- Molecule
- Plant-derived head-to-tail cyclic peptide scaffold with a cystine knot (typically 28-37 residues)
- Sequence length
- 29 amino acids
Handling
- Diluent
- Not applicable
- Lyophilised
- Room temperature is genuinely acceptable — thermal stability is the defining property of this class.
- Reconstituted
- Refrigerated; still far more stable in solution than a conventional peptide.
Mixing
Cyclotides are made by chemical ligation or recombinant expression with intein-mediated cyclisation; correct disulfide connectivity is the hard part of the synthesis and is not something a grey-market supplier can verify.
Side effects
- commonHaemolysis— Many native cyclotides including kalata B1 lyse red blood cells at higher concentrations — a real limitation for systemic use.
- commonUterine contraction— Kalata B1 is a uterotonic; this is literally how the class was discovered.
- uncommonCytotoxicity to mammalian cells— Membrane-disrupting activity is not fully selective for microbes and insects.
Do not use if
- Pregnancy - native cyclotides are uterotonic and were traditionally used to induce labour.
What to monitor
- · Not applicable.
Legal status
Not a regulated therapeutic. Plant sources are food-adjacent botanicals; engineered cyclotides are preclinical research materials.
References
- Craik et al. 1999, Journal of Molecular Biology — plant cyclotides as a unique family of cyclic knotted proteins (preclinical)
- Wang & Craik 2018, Nature Chemical Biology — designing macrocyclic disulfide-rich peptides as drug scaffolds (review)
Mechanism in depth
Plant-derived peptides with a head-to-tail cyclic backbone locked by a cystine knot - three disulphides threaded through each other. The result is exceptional resistance to heat, proteases and chemical denaturation, which is why they are pursued as scaffolds for grafting other sequences onto rather than as drugs in their own right.
What usually goes wrong
Native cyclotides are membrane-disruptive and cytotoxic - that is their function as plant defence molecules. Stability is not safety, and the two are routinely conflated when the class is described.
Receptor targets
- Varies with the grafted epitope; native cyclotides are membrane-active
Scaffold-dependent
Genuinely uncertain
- No cyclotide-based therapeutic has been approved.
- Cytotoxicity of native sequences limits which are usable as scaffolds.