Frequently Asked Questions
Everything you wanted to know about cyclopeptides — from the basic science to clinical applications and the companies bringing them to market.
What are cyclopeptides?
Start here if you're new to the field. These questions cover the fundamental science without assuming a biology background.
A cyclopeptide (also called a cyclic peptide) is a protein or peptide whose amino acid chain forms a closed ring — the two ends are joined by a covalent bond, creating a circle with no free termini. This simple structural difference makes cyclopeptides extraordinarily stable compared to normal (linear) peptides.
The most biomedically important subclass are cyclotides — plant-derived cyclopeptides that also contain an interlocking arrangement of three disulfide bonds called the Cyclic Cystine Knot (CCK). The combination of a cyclic backbone and the CCK gives cyclotides a level of structural stability unmatched by any other naturally occurring protein.
All cyclotides are cyclopeptides, but not all cyclopeptides are cyclotides. "Cyclopeptide" or "cyclic peptide" is the broad term for any peptide with a circular backbone — this includes cyclotides, orbitides, cyclosporin A, SFTI-1, and thousands of synthetic variants.
"Cyclotide" refers specifically to plant-derived cyclopeptides that combine a head-to-tail cyclic backbone with the Cyclic Cystine Knot (CCK) — three interlocking disulfide bonds formed by six conserved cysteine residues. The CCK gives cyclotides an additional layer of structural stability beyond simple backbone cyclisation. They are 28–37 amino acids in length and are found naturally in five plant families.
Cyclotides have been consumed by humans for centuries — the kalata-kalata tea containing kalata B1 was used by women in the Congo for generations as a labour accelerant, with no apparent adverse effects at natural doses.
Cyclotides appear to be non-toxic to vertebrates at the concentrations found in natural plant sources and at the therapeutic doses being investigated in clinical trials. The Sero-X biopesticide, derived from butterfly pea cyclotides, is registered by the Australian Pesticides and Veterinary Medicines Authority with no upper limit of use due to its exceptional safety profile and non-toxicity to mammals, birds, and pollinators.
Formal safety studies are underway as part of the clinical trial process for T20K (Phase I/II, multiple sclerosis), and early results have been encouraging. Like any pharmaceutical compound, therapeutic doses require proper clinical evaluation — but the natural history of human cyclotide exposure is reassuringly benign.
Cyclotides have been found in five plant families:
- Rubiaceae (the coffee family) — including the original kalata-kalata plant, Oldenlandia affinis
- Violaceae (violets) — a particularly rich source of cyclotide diversity, studied extensively by Prof. Ulf Göransson at Uppsala University
- Cucurbitaceae (cucumbers and squashes)
- Fabaceae (legumes) — including butterfly pea Clitoria ternatea, source of butelase-1
- Poaceae (grasses) — including rice, maize, and wheat at low levels, suggesting an ancient and widespread evolutionary origin
Individual plant species can produce dozens to hundreds of distinct cyclotide variants simultaneously, each with slightly different loop sequences and biological activities.
The first cyclotide — kalata B1 — was isolated by Norwegian physician Dr. Lorents Gran in 1973, from a plant used in traditional Congo birth practices. He had observed women drinking kalata-kalata tea to accelerate labour during his time as a Red Cross doctor in the Congo in the 1960s, and spent years identifying the active compound.
However, the analytical tools of the era could not reveal the cyclic structure, and Gran's papers went largely unnoticed for two decades. The cyclic cystine knot structure was not revealed until 1995, using NMR spectroscopy. The term "cyclotide" was coined in 1999, largely through the work of Professor David Craik's group at the University of Queensland, who established cyclotides as a distinct protein family and described the CCK motif. Read the full discovery story.
How do they work?
The structural biology behind cyclopeptide stability and why it matters for medicine.
Three structural features protect cyclopeptides from digestive enzymes:
- No free termini. The cyclic backbone eliminates the free N- and C-termini that exoproteases use as attack points. The very first step of protein digestion — exoprotease trimming from the ends — is physically impossible.
- The Cyclic Cystine Knot. In cyclotides, the CCK creates a rigid, compact 3D structure that endoproteases (which cut in the middle of chains) cannot unfold or access. The enzyme active site simply cannot make contact with the backbone.
- Covalent disulfide bonds. The three disulfide bonds in the CCK are covalent — they cannot be broken by the heat, acid, or reducing chemistry of the digestive tract. Under the non-reducing conditions of the gut, they remain locked.
Together these features make cyclotides resistant to boiling, stomach acid (pH 2), and every known digestive enzyme — including pepsin, trypsin, chymotrypsin, and the full complement of pancreatic proteases.
The CCK is the defining structural feature of cyclotides. It is formed by six cysteine residues in the cyclic backbone, which pair up to form three disulfide bonds (S–S bonds). These three disulfide bonds are arranged so that one pair threads through a ring formed by the other two — creating a true topological knot.
This is not just chemical stability; it is topological stability. The molecule would have to have covalent bonds broken to change shape — heat, acid, and enzymes cannot do this under physiological conditions. It is the same principle that makes a pretzel impossible to unloop without breaking it. The CCK, together with the cyclic backbone, produces the most structurally stable naturally occurring proteins known to science.
Drug grafting is the process of inserting a therapeutically active peptide sequence into one of the surface-exposed loops of a cyclotide scaffold. The cyclotide scaffold provides extraordinary stability — the grafted drug can be taken orally without being destroyed in the gut. The inserted therapeutic sequence delivers the desired biological effect once the molecule reaches its target.
This approach transforms any peptide drug that would normally require injection into a potential oral drug — a fundamental shift in how peptide medicines can be delivered. It was pioneered by Professor David Craik's group at UQ and is now the central concept in cyclotide pharmaceutical development. Examples include conotoxin grafts (100× more potent than gabapentin for pain), CXCR4-targeting grafts (HIV/cancer), and p53-activating grafts (cancer).
Cyclotides are 28–37 amino acids long, giving them a molecular weight of approximately 3,000–4,000 Daltons (3–4 kDa). This places them between the two dominant drug classes:
- Small molecule drugs (aspirin, statins, most pills) — typically <500 Da
- Antibody drugs (biologics, monoclonal antibodies) — typically ~150,000 Da (150 kDa)
This intermediate size is a key advantage. Cyclotides are small enough to be absorbed orally through intestinal epithelial tissue, yet large enough to interact with biological targets that small molecules cannot reach — including protein-protein interaction surfaces and intracellular targets. They occupy a therapeutic space that has historically been difficult to drug.
Yes — and this is one of the properties that makes them particularly valuable as drug candidates. Cyclotides are amphipathic (carrying both hydrophilic and hydrophobic regions on their surface), which allows them to interact with and partition into cell membranes. This property is also responsible for their natural insecticidal activity — they disrupt the gut membranes of pest insects.
In drug design, membrane permeability means cyclotide scaffolds can potentially reach intracellular targets that antibody drugs (which cannot cross cell membranes at all) and many small molecules cannot. This dramatically expands the range of diseases they could theoretically address.
Clinical applications and trials
Where the science stands today — from approved drugs to active clinical trials.
Yes — on two fronts:
- Cyclosporin A (cyclosporine), derived from a fungal cyclopeptide, has been used as an immunosuppressant in organ transplant surgery since 1983. It is one of the most widely used drugs in transplant medicine and remains in the top tier of immunosuppressant prescriptions globally. Annual sales have historically exceeded $1 billion.
- Sero-X, a cyclotide-based biopesticide derived from butterfly pea (Clitoria ternatea), is commercially available in Australia for cotton, macadamia, and vegetable crops. It is the world's first commercial product based on plant cyclotide technology.
For plant-derived cyclotide pharmaceuticals specifically, the most advanced candidate is T20K (based on kalata B1), which is in Phase I/II human clinical trials for multiple sclerosis — taken orally.
T20K is in human clinical trials for MS now. Clinical trial timelines vary, but Phase I/II trials typically take 2–5 years, followed by Phase III trials and regulatory review before approval.
A realistic timeline for the first plant-derived cyclotide drug approval would be the late 2020s to early 2030s, depending on trial outcomes. For functional food applications — like those being developed by Phyllome, which involves delivering therapeutic cyclotide sequences through engineered edible plants — regulatory pathways may be faster than full pharmaceutical drug approval, potentially bringing consumer products to market earlier.
Companies and products
The commercial landscape — from Australian startups to major pharma partnerships.
Phyllome is an Australian startup based in Sydney that grows therapeutic cyclopeptides inside edible plants using indoor robotic vertical farming. The concept: engineer an edible plant (like a potato or salad green) to produce a therapeutic cyclotide sequence, then grow that plant at scale and process it into a consumer functional food product.
Because cyclotides survive digestion intact, the patient receives a therapeutic dose simply by eating the food — no pills, no injections, no pharmaceutical manufacturing chain. Phyllome partners with Professor David Craik's group at UQ's Institute for Molecular Bioscience and Australian supplements manufacturer Pharmacare. Visit phyllome.com for more.
Sero-X is the world's first commercial product based on cyclotide technology. It is a biopesticide developed by Australian company Innovate Ag in partnership with Professor David Craik's group at the University of Queensland.
It is derived from butterfly pea (Clitoria ternatea) plant extract and is registered by the Australian Pesticides and Veterinary Medicines Authority (APVMA) for use on cotton, macadamia, and vegetable crops. Sero-X is approved with no upper limit of use and is non-toxic to bees, pollinators, birds, and vertebrates — making it one of the safest pesticides on the market and a demonstration of cyclotide technology at commercial scale.
The field has grown rapidly. Key players include:
- Phyllome (Australia) — plant pharming of therapeutic cyclotides as functional foods
- Innovate Ag (Australia) — Sero-X biopesticide, first commercial cyclotide product
- Cyxone AB (Sweden) — T20K/MS Phase I/II clinical trial
- Circle Pharma (USA) — $117.5M raised for macrocyclic peptide drug discovery
- Insamo (USA) — $12M seed round for AI-designed cyclic peptides
- Unnatural Products (USA) — $220M deal with Merck for cyclic peptide discovery
- CyclicTx (USA) — AI-driven cyclic peptide design platform
- Roche/Chugai — major pharma investment in cyclic peptide oral drug programs
See our full companies page for a comprehensive overview of the global industry.
The Glossary defines every technical term used across this site. The Science page explains the CCK, oral bioavailability, and drug grafting in full detail. And the Discovery page tells the full story from the Congo to the clinic.