What Is Cyclosporins? Definition and What Research Reports

Definition

Cyclosporins are a family of naturally occurring cyclic undecapeptides — eleven amino acid residues joined head-to-tail into a closed macrocyclic ring — produced by filamentous fungi and characterised by a heavily N-methylated peptide backbone. The most widely studied member is cyclosporin A (also written ciclosporin, cyclosporine or CsA), and it sits at the head of an alphabetically lettered series of naturally occurring congeners; a 2021 review in Journal of Medicinal Chemistry surveyed cyclosporin structure and permeability across that series "from A to Z and beyond," including semi-synthetic derivatives (PMID 34478303). As a glossary term, "cyclosporins" therefore refers to a structural class of fungal peptide natural products, not to a single molecule.

What Class of Molecule Are They?

Cyclosporins are peptides by composition but behave chemically more like small-molecule macrocycles than like the linear peptides used in most research settings. They are non-ribosomal peptides: rather than being translated from mRNA, they are assembled residue-by-residue by a very large multi-domain enzyme. Researchers reviewed the biosynthesis of cyclosporins alongside other natural peptidyl-prolyl cis/trans isomerase inhibitors, placing the compound family within a broader group of fungal peptide natural products that engage the same enzyme class (PMID 25497210). The assembling enzyme itself, cyclosporin synthetase, has been isolated for study, and one report described an improved purification procedure for cyclosporin synthetase to make the enzyme more tractable for biochemical work (PMID 16139518).

Because the natural scaffold is fixed by that enzymatic assembly line, much of the chemistry literature focuses on modifying the finished ring. A 2015 review in Biochimica et Biophysica Acta covered the semi-synthesis of cyclosporins — chemical modification of the fermented natural product to generate analogues that would be difficult to obtain by fermentation alone (PMID 25707381). Microbial biotransformation is a related route: one analytical study structurally characterised cyclosporin A, cyclosporin C and the microbially bio-transformed analogue AM6 (PMID 24725868).

The Cyclosporin Family at a Glance

How the Term Is Used in Peptide Research

Within peptide science, cyclosporins are cited in three broad contexts.

1. As a reference macrocycle for permeability and conformation

Cyclosporins are the textbook example of a peptide that crosses membranes despite its size, and the literature attributes this to conformational behaviour rather than to size alone. The 2021 Journal of Medicinal Chemistry review examined the relationship between cyclosporin structure and permeability across natural and modified members of the family (PMID 34478303). A central idea in that work is the ability of the ring to adopt different conformations depending on environment; researchers used mass spectrometry to detect conformation types of cyclosporin that retain intramolecular hydrogen bonds, which is the structural feature commonly invoked to explain how the molecule shields its polar backbone (PMID 25064599).

2. As a probe of peptidyl-prolyl isomerases (cyclophilins)

Cyclosporins are grouped in reviews with other natural peptidyl-prolyl cis/trans isomerase inhibitors, a classification based on the protein family they bind (PMID 25497210). That binding property has been used to identify partner proteins in other organisms: one study reported the identification of cyclosporin-binding proteins in Plasmodium falciparum, the malaria parasite (PMID 12906882).

3. As an analytical challenge

Distinguishing cyclosporin variants is difficult because many share the same mass or differ only in conformation, so the family appears frequently in analytical-chemistry method papers. One study combined differential mobility spectroscopy, mass spectrometry and hydrogen–deuterium exchange to separate isomers, conformers and analogues of cyclosporin (PMID 32698568). Another described identification of isocyclosporins using collision-induced dissociation of doubly protonated species (PMID 33592699), and a third used HPLC–ESI–ion-trap mass spectrometry for structural characterisation of cyclosporin A, cyclosporin C and the bio-transformed analogue AM6 (PMID 24725868).

What the Published Literature Reports

The verified studies summarised here span chemistry, microbiology and clinical description. On the structural side, a 2020 study in Biochemical and Biophysical Research Communications compared cyclosporin variants B through E on the basis of their structural properties and their activity in mitochondrial membranes, treating the natural congeners as a structure–activity series rather than as impurities (PMID 32307084).

On the microbiological side, a 2023 study in Foods examined the effect of cyclosporin A on the food-spoilage mould Aspergillus niger and investigated the possible mechanisms involved (PMID 36766095). The parasitology literature contributes a complementary observation: the study of Plasmodium falciparum reported the identification of cyclosporin-binding proteins in that organism (PMID 12906882).

In the human literature, a report in Oxidative Medicine and Cellular Longevity described long-term results with cyclosporine A in patients with Ullrich congenital muscular dystrophy, a rare inherited muscle disorder (PMID 22028947). Cyclosporine A is a regulated prescription medicine in the United States and elsewhere; it is not a research chemical, and its clinical use is governed by approved product labelling.

Adverse Events: What Studies Report

The verified papers indexed for this entry are predominantly chemical, biosynthetic and analytical — covering semi-synthesis (PMID 25707381), biosynthesis (PMID 25497210) and mass-spectrometric characterisation (PMID 32698568) — and they do not report safety outcomes, tolerability data or adverse-event rates. The only clinical entry in this set is the long-term description of cyclosporine A in Ullrich congenital muscular dystrophy (PMID 22028947). Readers looking for the safety profile of an approved cyclosporine product should consult that product's regulatory labelling and the broader clinical literature, neither of which is summarised here.

Notes on Terminology

• Spelling. "Cyclosporin," "cyclosporine" and "ciclosporin" appear interchangeably across journals; the analytical literature uses all three for the same scaffold (PMID 34478303).
• Singular vs. plural. "Cyclosporin A" names one compound; "cyclosporins" names the family, including lettered natural variants (PMID 32307084).
• Iso- prefix. Isocyclosporins are structural rearrangement products of the parent ring, identified by tandem mass spectrometry rather than by simple mass measurement (PMID 33592699).

This page is for educational purposes only and is not medical advice; consult a licensed physician about any medical question, condition or medication. Nothing here describes how any substance should be obtained, prepared or administered.

References

• Semi-synthesis of cyclosporins (Biochimica et Biophysica Acta, 2015)
• Biosynthesis of cyclosporins and other natural peptidyl prolyl cis/trans isomerase inhibitors (Biochimica et Biophysica Acta, 2015)
• An improved purification procedure for cyclosporin synthetase (Protein Expression and Purification, 2006)
• Cyclosporin Structure and Permeability: From A to Z and Beyond (Journal of Medicinal Chemistry, 2021)
• Comparison of cyclosporin variants B-E based on their structural properties and activity in mitochondrial membranes (Biochemical and Biophysical Research Communications, 2020)
• Detection of conformation types of cyclosporin retaining intramolecular hydrogen bonds by mass spectrometry (Analytical and Bioanalytical Chemistry, 2014)
• Separating Isomers, Conformers, and Analogues of Cyclosporin using Differential Mobility Spectroscopy, Mass Spectrometry, and Hydrogen-Deuterium Exchange (Analytical Chemistry, 2020)
• Identification of isocyclosporins by collision-induced dissociation of doubly protonated species (Talanta, 2021)
• Structural characterization of cyclosporin A, C and microbial bio-transformed cyclosporin A analog AM6 using HPLC-ESI-ion trap-mass spectrometry (Talanta, 2014)
• The Effect of Cyclosporin A on Aspergillus niger and the Possible Mechanisms Involved (Foods, 2023)
• Cyclosporin-binding proteins of Plasmodium falciparum (International Journal for Parasitology, 2003)
• Cyclosporine A in Ullrich congenital muscular dystrophy: long-term results (Oxidative Medicine and Cellular Longevity, 2011)