Cyclopeptides in Medicine

From the transplant wards where cyclosporin has saved lives since the 1980s, to the oral MS drug in clinical trials today, cyclopeptides span the full spectrum of pharmaceutical development — approved products, clinical trials, and a rich pipeline targeting some of medicine's hardest problems.

Drug Design Advantage

Why the Pharmaceutical Industry is Excited

Cyclopeptides occupy a unique niche in the drug design landscape — too large to be ignored like small molecules, too stable and simple to be confused with antibodies.

Drug developers face a frustrating middle ground: small molecules are easily swallowed but can only hit a narrow range of biological targets. Large biologics like antibodies can hit almost any target, but they must be injected, are expensive to manufacture, and break down in the gut. For decades, a vast category of biologically important targets — protein-protein interactions, intracellular signalling molecules, membrane receptors — remained essentially out of reach for conventional drugs. Cyclopeptides offer a way through this wall. Their circular backbone confers extraordinary stability against heat, acid, and the digestive enzymes that destroy ordinary proteins. Their compact size (typically 14–37 amino acids) allows them to cross cell membranes in ways larger biologics cannot. And, critically, some cyclotides survive oral delivery entirely intact — arriving in the bloodstream after being swallowed, not injected. No other class of protein-based molecule has convincingly demonstrated this.

Perhaps the most powerful concept to emerge from the last two decades of cyclotide research is molecular grafting. Rather than searching nature for a cyclotide that happens to have a desired therapeutic activity, chemists can design the activity they want and then transplant it into a cyclotide scaffold. The cyclotide — typically the well-studied plant peptide kalata B1 — acts as a stable, bioavailable chassis. An active peptide sequence (derived from a hormone, a venom toxin, or a receptor ligand) is inserted into one of the cyclotide's exposed loops. The result is a chimeric molecule that carries the therapeutic payload of the inserted sequence, but with the oral bioavailability, stability, and membrane permeability of the cyclotide scaffold. This grafting strategy has been used to engineer cyclopeptide candidates for chronic pain, HIV, multiple sclerosis, obesity, and cancer.

The pipeline today reflects four decades of cumulative progress. Cyclosporin A — a cyclic peptide from a soil fungus — was approved in 1983 and became a blockbuster immunosuppressant that made modern organ transplantation possible. For the next twenty years, it stood almost alone as proof of the class's pharmaceutical value. Then, from the early 2000s, David Craik's group at the University of Queensland began systematically characterising cyclotides and developing grafting technology. By 2020, the first cyclotide-derived drug candidate had entered human clinical trials. Today, preclinical programmes targeting pain, cancer, HIV, obesity, and antimicrobial resistance are in laboratories across Australia, Europe, Japan, and the United States. The field has gone from a single approved drug to a genuine therapeutic pipeline.

Therapeutic Pipeline

Applications by Disease Area

From a landmark approved drug to a growing bench of clinical and preclinical candidates, cyclopeptides are active across medicine's most challenging therapeutic areas.

Organ Transplant Immunosuppression

Cyclosporin A (cyclosporine) — derived from the soil fungus Tolypocladium inflatum — was discovered in 1969 and approved for clinical use in 1983. It remains one of the most commercially significant cyclic peptides ever identified. Used worldwide to prevent organ rejection after transplant surgery and to treat autoimmune conditions including rheumatoid arthritis and psoriasis, cyclosporin achieved annual sales historically exceeding $1 billion. Its success is the clearest proof that cyclopeptides are not merely a scientific curiosity — they are capable of reaching commercial scale and saving lives at a global level.

Approved

Multiple Sclerosis

[T20K]kalata B1 is an engineered cyclotide developed by Prof. Christian Gruber's group at the Medical University of Vienna and licensed to Swedish biotech Cyxone AB. A single amino acid modification — threonine replaced by lysine at position 20 — confers potent immunomodulatory activity. In animal models of MS, T20K halted disease progression. Now in Phase I/II human clinical trials, the drug is designed to be taken orally. This makes T20K the first plant-derived cyclotide to enter human clinical testing — a landmark moment for the entire field.

Clinical Trial

Chronic Pain

Prof. David Craik's group at the University of Queensland has grafted therapeutic sequences derived from cone snail venom peptides (conotoxins) into cyclotide scaffolds. Conotoxins are among the most potent naturally occurring pain-blocking molecules known, but they cannot survive oral delivery. Embedded in a cyclotide chassis, the grafted compound demonstrated activity 100× more potent than gabapentin — a leading neuropathic pain drug — at equivalent doses in animal studies. Crucially, this was achieved with oral delivery potential, positioning it as a possible non-opioid alternative for chronic pain management.

Advanced Research

Cancer / Oncology

Oncology is the most active area of the broader cyclic peptide industry. Approaches include: naturally occurring cyclotides with direct cytotoxic activity against cancer cell lines; grafted cyclotide scaffolds targeting cancer-specific surface receptors including CXCR4; and macrocyclic peptide platforms targeting intracellular oncology targets such as the p53-MDM2 axis — protein-protein interactions that conventional small molecules cannot block. US company Unnatural Products has a $220M collaboration with Merck for oncology applications (2023), signalling major pharma's conviction in the class.

Active Research

Obesity & Appetite Regulation

Satiety-signalling peptide sequences grafted into cyclotide scaffolds are being expressed in edible plants as part of a collaboration between Prof. David Craik's lab (UQ) and Sydney-based startup Phyllome. The concept replaces the pill or injection entirely: a patient eats a small serving of a modified potato product and receives a measurable therapeutic dose of appetite-suppressing peptide. The plant itself serves as the delivery vehicle. Oral bioavailability via food — not pharmaceutical manufacturing — is the core innovation. Partnership with Australian supplements leader Pharmacare supports the commercialisation pathway.

Active Research

HIV / Antiviral

Multiple naturally occurring cyclotides demonstrate anti-HIV activity in cell culture. Prof. Julio Camarero at the University of Southern California has engineered a CXCR4-antagonist cyclotide — CXCR4 being a co-receptor required for HIV entry into cells. Blocking CXCR4 prevents the virus from establishing infection. Combined with the oral bioavailability potential of the cyclotide scaffold, this approach could eventually offer a once-daily oral antiviral — though it remains early-stage research and has not yet entered human trials.

Active Research

Cardiovascular / Cholesterol

Cyclotide scaffolds targeting cholesterol regulation are being developed as complementary plant-based alternatives to statins — one of the most widely prescribed drug classes in the world. This work is part of Phyllome's functional food pipeline, developed in partnership with the University of Queensland and Pharmacare. The model is similar to the obesity programme: therapeutic peptides expressed in food plants, delivered via consumption rather than pharmaceutical dosage forms. At the right dose and with regulatory approval, plant-based cholesterol management could reach consumers as a functional food rather than a medicine.

Active Research

Antimicrobial

Multiple cyclotides demonstrate antibacterial and antifungal activity. The Göransson lab at Uppsala University (Sweden) has developed cyclotide-based antimicrobial scaffolds as potential alternatives to conventional antibiotics — an area of acute global urgency given the accelerating crisis of antibiotic resistance. Cyclotides' membrane-disrupting mechanism of action differs fundamentally from most existing antibiotics, which means they may retain activity against multi-drug-resistant organisms. Optimising spectrum, potency, and safety for clinical use remains an active area of research.

Active Research

Agriculture / Biopesticides

Sero-X — commercialised by Innovate Ag in 2017 — is the world's first commercial cyclotide product and the first organic insecticide derived from butterfly pea (Clitoria ternatea) plant extract. Registered by the Australian Pesticides and Veterinary Medicines Authority for cotton, macadamia, and vegetable crops, Sero-X is approved with no upper limit of use. It is non-toxic to bees, beneficial insects, and vertebrates. Developed in partnership with Prof. David Craik's group under an ARC Linkage Grant, Sero-X is proof that cyclotide plant production can reach commercial scale — and that doing so is economically viable.

Commercial
Historical Arc

A Pipeline Two Decades in the Making

The story of cyclopeptide therapeutics begins not in a laboratory but in a Norwegian field. Kalata-kalata, a traditional Congolese remedy made from the plant Oldenlandia affinis, was studied by Norwegian physician Lorents Gran in the 1970s. The active ingredient — kalata B1 — was structurally characterised by David Craik's group in 1995. That discovery opened a door. But the clinical pipeline that has since emerged required another full generation of scientific work.

In 1983, cyclosporin A — a cyclic peptide from a soil fungus, not a plant — became the first cyclopeptide approved as a pharmaceutical. For the next two decades it stood essentially alone. The broader scientific community was aware of cyclotides' structural elegance, but the question of whether they could serve as drug scaffolds remained open. The grafting concept — inserting therapeutic sequences into cyclotide loops — was pioneered in Craik's lab through the 2000s. It produced the first proof-of-concept that engineered cyclotides could carry bioactive payloads and survive oral delivery. By the early 2010s, programmes targeting pain, HIV, and immunomodulation were underway.

In 2020, T20K entered Phase I human clinical trials — the field's first human test of a plant-derived cyclotide drug. That milestone came roughly 25 years after kalata B1's structural characterisation and nearly 50 years after Lorents Gran's field observations. Progress in medicinal chemistry is rarely fast. But the gap between zero clinical candidates (circa 2000) and a genuine multi-disease therapeutic pipeline (today) represents one of the more remarkable maturation stories in contemporary pharmacology.

Historical Milestone

"Cyclosporin A has saved hundreds of thousands of lives in transplant surgery since 1983. It is a cyclopeptide — proof that this class of molecule can be a mainstream pharmaceutical."

The agricultural success of Sero-X (2017) added a further dimension: demonstrating that cyclotide production at commercial scale is not merely a laboratory aspiration. If plants can be grown and harvested to produce a registered crop protection product, the same infrastructure logic applies — with appropriate regulatory modification — to therapeutic applications in food and medicine. Phyllome's functional food programme represents the next iteration of that same idea.

Key references: Craik DJ et al. (1999) Science 281(5383):1873; Gould A et al. (2011) Chemistry & Biology; Gruber CW (Medical University Vienna) — T20K patent and Cyxone AB licensing. Market data: Global Cyclic Peptides Market Report, 2024.

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Who is Building This Future?

The therapeutic applications described here are being commercialised by a growing global industry — from clinical-stage biotechs in Sweden to plant-based functional food companies in Australia.

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