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A Soil Sample From Norway: The Story of Cyclosporine, the Cyclic Peptide That Changed Transplants
Few drug discovery stories begin as casually as this one. A Swiss company asked its employees to bring back soil from their vacations. One sample, from a Norwegian plateau, contained a fungus whose product would make organ transplants routine.
Key takeaways
- Sandoz in Basel collected soil from around the world to search for new natural products.
- A fungus from a Norwegian sample produced a peptide that Jean-Francois Borel found suppressed immune responses in 1972.
- The molecule, cyclosporine, is a ring of eleven amino acids, several of them modified.
- Its structure explains why it survives in the body better than most peptides.
- It was first used in transplant patients in the late 1970s and approved in the United States in 1983.
Postcards from the soil
In the 1960s, drug companies searched the natural world for chemistry they could not invent. Sandoz asked staff to collect soil samples when they traveled. Back in Basel, fungi from those samples were grown and tested for useful effects.
One soil sample, from the Hardangervidda plateau in Norway, produced a fungus that made a mixture of compounds. At first, it looked like a modest antifungal. The screening tests were broad, though, and that is where the real finding appeared.
The surprise
Jean-Francois Borel ran tests that looked for the ability to dampen immune responses without simply killing cells. In 1972 he found that one compound from the fungus did exactly that. It suppressed the activity of immune cells in a targeted way, and it was far less toxic to bone marrow than the immunosuppressants then available.
A peculiar ring
When chemists worked out the structure, they found a cyclic peptide of eleven amino acids. It did not look like ordinary peptides. Several of the amino acids carry an extra methyl group on the backbone nitrogen, and one is the mirror-image form of an amino acid, which normal proteases do not recognize well.
These features do three things. The ring removes the free ends that enzymes like to chew. The methyl groups hide polar groups and make the molecule more fat-soluble. And the mirror-image amino acid helps hold the shape. The combination makes cyclosporine unusually stable for a peptide, and it can be taken by mouth. Our posts on cyclic peptides and terminal modifications explain the design principles.
To the clinic
Cyclosporine was tested in animal transplants and then, in the late 1970s, in people, including early work at Cambridge led by the surgeon Roy Calne. Survival of transplanted kidneys improved sharply, and liver and heart transplants became far more practical. It was approved in the United States in 1983.
What it teaches peptide chemists
Cyclosporine broke a rule of thumb that said large molecules rarely become oral drugs. Chemists now study how folding, hidden polarity and N-methylation can let big molecules cross membranes. It also shows why stability is designed, not assumed. See half-life engineering and hydrolysis hotspots.
The bottom line
A casual request for souvenirs led to a molecule that made modern transplant medicine possible. Not every discovery needs a grand plan, but every one needs careful follow-up. Read about how we document our own compounds on the COA page.
Related reading
- Cyclic peptides and macrocycles
- Half-life engineering
- History of peptide drugs
- Browse the full Research Library
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.