The Science of Circular Proteins

Nature's most
stable molecules

Cyclopeptides are circular proteins found in plants that survive boiling, acid, and digestion intact. Discovered in an African rainforest tea, they are now at the frontier of medicine — delivering drugs orally that once required injections.

Explore the Science → The Discovery Story
50,000+ Estimated cyclotides in nature
1960s First isolated from rainforest tea
3 Disulfide bonds in the cystine knot
Oral Demonstrated bioavailability
Human Clinical trials now underway

What are cyclopeptides?

Circular proteins that
rewrite the rules of biology

Most proteins are linear chains — think of them as a rope with two free ends. Those ends are exactly where enzymes attack, unravelling the chain. Cyclopeptides have no ends. Their amino acid chain loops back on itself, forming an unbroken ring.

The most remarkable subclass — cyclotides — go further. Six cysteine residues in the ring form three interlocking disulfide bonds, creating a structure called the Cyclic Cystine Knot (CCK). The result is a molecular architecture so compact and interlocked that it withstands boiling water, stomach acid, and the full battery of digestive enzymes.

Found in plants across five unrelated families — from the African Rubiaceae to European violets to legumes — cyclotides appear to have evolved independently multiple times, suggesting nature repeatedly converged on this structure because it is extraordinarily useful.

  • 🔁
    Head-to-tail circular backbone No free N- or C-terminal ends for proteases to attack
  • 🔗
    Three interlocking disulfide bonds The Cyclic Cystine Knot adds physical rigidity — enzymes cannot unfold it
  • 🌿
    Found in everyday plants Violets, butterfly pea, sunflowers, legumes, and hundreds more
  • 💊
    The ideal drug scaffold Stable, membrane-permeable, and small enough (~3 kDa) to be absorbed orally
  • 🏭
    Growable in crop plants Engineered plants can act as living drug factories — no fermentation tanks required

Explore the topics

Everything you need to know

From the molecular structure that makes them extraordinary, to the researchers who discovered them, to the companies turning them into medicines.

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The Science of Cyclopeptides

How the Cyclic Cystine Knot works, the difference between cyclotides and orbitides, and why the closed ring is the most important shape in drug delivery.

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Why They Survive Digestion

Most protein drugs are destroyed in the stomach. Cyclopeptides are not. Discover the structural properties that make oral delivery possible — and how scientists are using this to replace injections.

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The Discovery Story

From a 1960s Congo rainforest — where women brewed a tea to accelerate labour — to the NMR spectroscopy breakthrough that revealed the cyclic structure. The history of the most remarkable molecules in plants.

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Growing Cyclopeptides in Plants

How researchers engineer crop plants to act as sunlight-powered bioreactors — producing therapeutic cyclopeptides in potatoes, sunflowers, and soybeans at agricultural scale.

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Medical Applications

Multiple sclerosis. Chronic pain. Cancer. Obesity. HIV. A survey of the therapeutic applications in development — from human clinical trials to the cyclopeptide already in transplant wards worldwide.

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The Global Industry

The companies commercialising cyclopeptides around the world — from Australia's Phyllome and Innovate Ag, to US biotechs Circle Pharma and Insamo, to the $220M Merck deal reshaping oncology drug design.

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The breakthrough

Ending the needle for biological drugs

For decades, the pharmaceutical industry has faced a fundamental problem: the most powerful biological medicines — peptides and proteins — are destroyed in the gut before they can reach their targets. That forces patients onto injections for life.

Cyclopeptides break this rule. Their closed-ring backbone and interlocking disulfide bonds make them impervious to the digestive enzymes that destroy linear peptides. Researchers have demonstrated that therapeutic sequences can be grafted into a cyclotide scaffold, borrowing its stability to make any peptide drug orally deliverable.

[T20K]kalata B1 — a single-point mutant of the naturally occurring kalata B1 cyclotide — is currently in human clinical trials for multiple sclerosis, taken as an oral dose.

How it works →

Linear peptide drugs

Exposed N- and C-termini attacked by aminopeptidases and carboxypeptidases
Unfolded by pepsin in the stomach within minutes
Degraded further by trypsin and chymotrypsin in the intestine
Must be injected — bioavailability <1% orally

Cyclopeptides

No free termini — backbone cyclisation removes all protease entry points
Cystine knot physically prevents enzyme unfolding
Survives boiling water, stomach acid, and intestinal enzymes intact
Demonstrated oral bioavailability comparable to clinical-stage drugs
Kalata B1 has shown oral bioavailability in human clinical trials for multiple sclerosis

The scientists behind the science

A global research community

Cyclopeptide science spans six decades and five continents. These are the researchers who built our understanding of circular proteins — from first isolation in the Congo to clinical trials in Sweden.

Prof. David Craik

Institute for Molecular Bioscience, University of Queensland — Australia

Cyclotide family characterisation • Drug grafting • Plant pharming

The world's foremost authority on cyclotides. Craik's group at IMB UQ established cyclotides as a protein family, characterised the Cyclic Cystine Knot motif, and pioneered the drug-grafting technique that lets any therapeutic peptide borrow cyclotide stability — making oral delivery of biologics possible. His team of ~35 researchers have active projects in pain, obesity, and cancer, partnering with Pfizer, Roche, AstraZeneca, and Takeda. He also directs the ARC Centre of Excellence for Innovations in Peptide and Protein Science (CIPPS) and the Clive and Vera Ramaciotti Facility for Producing Pharmaceuticals in Plants.

Royal Society Fellow (2021) King's Birthday Award (2023) ARC CIPPS Director
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Dr. Lorents Gran

Norwegian Red Cross — Norway

Discoverer of Kalata B1 (1973)

In the 1960s, working as a Red Cross physician in the Congo, Gran noticed local women drinking tea from Oldenlandia affinis to accelerate labour. He spent years isolating and publishing on the active peptide — naming it kalata B1 after the local plant name. Its cyclic structure went unexplained for over 20 years, until NMR revealed why this molecule survived boiling and digestion intact. Gran is the discoverer of the first cyclotide.

Discovery story →

Prof. Christian W. Gruber

Medical University of Vienna — Austria

Global biodiversity • T20K clinical trial • GPCR design

Led the Global Cyclotide Adventure — surveying 340+ flowering plant species across five continents to map cyclotide distribution. His group engineered T20K, a kalata B1 analogue that halted MS progression in animal trials and advanced to human clinical trials, licensed to Cyxone AB. Named Inventor of the Year 2015 at MedUni Vienna.

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Prof. Marilyn Anderson

La Trobe University — Australia

Biosynthesis • Gene structure • Crop plant cyclotides

Made foundational discoveries in cyclotide biosynthesis — demonstrating that cyclotides are encoded by single genes and that cyclization occurs in plant vacuoles. She discovered cyclotide-like sequences in graminaceous crops including rice, maize, and wheat, suggesting an ancient and far broader evolutionary origin than previously known.

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Prof. Ulf Göransson

Uppsala University — Sweden

European violet cyclotides • Antimicrobials • Synthesis

A direct bridge between the Craik and Gruber labs — Göransson did his PhD at Uppsala and postdoctoral work at UQ before founding his own group. His lab leads world-class discovery of cyclotides from European violets (Violaceae) and develops novel antimicrobial cyclic peptide scaffolds as alternatives to conventional antibiotics.

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Prof. James P. Tam

Nanyang Technological University — Singapore

Butelase-1 discovery • Enzymatic cyclization

Tam's group discovered butelase-1 from butterfly pea (Clitoria ternatea) — the first Asn/Asp-specific peptide ligase and fastest peptide ligase known. It cyclises peptide backbones with >95% yield, 20,000 times faster than the previously standard sortase A enzyme, transforming how cyclotides and cyclic peptides are produced in the lab.

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Prof. Julio A. Camarero

University of Southern California — USA

Chemical synthesis • Drug grafting • Cancer & HIV scaffolds

A leader in the chemical synthesis and biological engineering of cyclotides. Camarero pioneered grafting scaffolds targeting CXCR4 (HIV/cancer), p53, and RAS/RAF signalling pathways. His "plug and play" grafting approach bypasses difficult oxidative folding steps, producing grafted cyclotides with nanomolar GPCR affinities for drug discovery.

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Prof. Norelle Daly

James Cook University — Australia

NMR structural biology • Cyclic cystine knot architecture

Central to the structural characterisation of cyclotides by NMR spectroscopy, Daly's work underpins our 3D understanding of the cyclic cystine knot and its plasticity for drug design. She co-founded Paragen Bio, a startup commercialising disulfide-rich peptide drug discovery based on this structural knowledge.

Full profile →

Explore individual researcher profiles, their key papers, and active projects — see all researchers →

The global industry

Companies turning science into medicine

From functional foods grown in robotic farms to $220M oncology deals, cyclopeptides are moving from research labs into the commercial world.

Plant-based functional foods
Phyllome
Sydney, Australia

Phyllome grows therapeutic cyclopeptides directly inside edible plants using indoor robotic vertical farms — creating functional foods that deliver measurable health benefits without pills or injections.

In partnership with Prof. David Craik at UQ's IMB and Australian supplements leader Pharmacare, Phyllome is the first company to commercialise cyclotide technology in consumer functional foods, targeting pain, cholesterol, and obesity.

Functional Foods Cyclotides ARC Linkage Partner
Visit phyllome.com →
Innovate Ag
Australia

Commercialised Sero-X — the world's first cyclotide-based commercial product. The organic biopesticide is derived from butterfly pea and approved for use with no upper limit, safe for bees and pollinators.

Biopesticide Agriculture
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Circle Pharma
San Francisco, USA

$117.5M raised to develop macrocyclic peptides that penetrate cells and hit intracellular drug targets previously considered undruggable.

Oncology Macrocycles
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Insamo, Unnatural Products, CyclicTx, Chugai/Roche and more — see the full global industry overview →

The future of medicine
grows in a field

For the first time, the therapeutic compounds of the future can be grown in crop plants, harvested, and consumed as food. Cyclopeptides are not just a scientific curiosity — they are a new category of medicine.

Start with the science → Visit Phyllome →