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Synonym name: Ciclosporin; Ramihyphin A; Sandimmun; Sandimmune
Catalogue No.: BP0438
Cas No.: 59865-13-3
Formula: C62H111N11O12
Mol Weight: 1202.64
Botanical Source: Metab. of Trichoderma inflatum NRRL 8044 (previously Trichoderma polysporum). Also Fusarium solani and Tolypocladium sinense
Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams.
For Reference Standard and R&D, Not for Human Use Directly.
Inquire for bulk scale.
Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃
226.7500
3.5000
3.5000
Low
90.0000
No
No
No
No
No
No
Cyclosporin A (CsA) is an immunosuppressant with significant clinical value, first isolated from the fungus Tolypocladium inflatum in the 1970s. CsA, with its unique immunomodulatory effects, especially its significant effect in inhibiting T cell activation and cytokine release, has become a milestone drug for the prevention and treatment of organ transplant rejection. With deeper research, the potential applications of CsA in autoimmune diseases such as rheumatoid arthritis, psoriasis, and Sjögren's syndrome have gradually been revealed. This paper will systematically review the chemical structure and physicochemical properties, sources and extractions, pharmacological activity, mechanism of action, druggability evaluation, and clinical application prospects of cyclosporine A, aiming to provide reference for natural product pharmacology and related clinical research.
Cyclosporin A is a cyclic undecay peptide with a molecular formula C62H111N11O12 and a molecular weight of about 1202.61 Da. Its structure consists of 11 amino acid residues, forming a highly hydrophobic cyclic conformation. The LogP value of CsA is 3.5, indicating moderate lipid solubility, which facilitates penetration of cell membranes but limits its water solubility. Its topological pole surface area (TPSA) is 226.75 Ų, with 12 hydrogen bond acceptors, demonstrating strong polarity and hydrogen bonding ability, which significantly affect its binding to target proteins and pharmacokinetic properties.
The structural characteristics of CsA enable it to bind with high affinity for cyclophilin A (PPIA) within cells, forming complexes that inhibit the activity of protein phosphatase 2B (PP2B, also known as calcineurin). The IC50 of this inhibitory effect is about 7 nM, showing an extremely high potency. Additionally, CsA can inhibit integrin LFA-1 (CD11a/CD18)-mediated cell adhesion, further modulating immune cell function.
Cyclosporin A was originally produced by fermentation of the fungus Tolypocladium inflatum (formerly Trichoderma polysporum). This fungus belongs to the Ascomycota phylum and can synthesize CsA in specific media. Traditional production processes mainly rely on fermentation technology, using solid or liquid fermentation to optimize cultivation conditions (such as carbon source, nitrogen source, pH, temperature, dissolved oxygen, etc.) to increase yield.
Extraction methods typically include filtration, solvent extraction, and purification of the fermentation broth. Common solvents include organic solvents such as ethyl acetate and methanol. Purification steps often use silica gel column chromatography, high-performance liquid chromatography (HPLC), and other techniques to obtain high-purity CsA. In recent years, with advances in fermentation engineering and molecular biology technologies, genetic engineering to modify strains and optimize fermentation processes has significantly improved both CsA yield and purity.
The core pharmacological action of cyclosporine A is immunosuppression, mainly by suppressing T cell-mediated immune responses. CsA can effectively block T cell receptor (TCR) signaling transduction, inhibit the production of pro-inflammatory cytokines such as IL-2, thereby weakening the proliferation and activation of immune cells. Its main indications include the prevention and treatment of organ transplant rejection, as well as various autoimmune diseases.
In rheumatoid arthritis (RA), CsA exerts anti-inflammatory and immunomodulatory effects by modulating multiple signaling pathways. Related targets include AMPK (PRKAA1), BCL2, NOTCH1, TLR4, STAT3, ABCG2, PRKCA, ALOX5, PRKCD, and NFE2L2. CsA can inhibit the expression of pro-inflammatory factors, reduce joint inflammation and tissue destruction, and clinical studies have shown certain efficacy in improving RA symptoms and delaying disease progression.
CsA binds to cyclophin, inhibits calcineurin (PPP3CA) activity, blocks the NFAT (nuclear factor-activated T cell) signaling pathway, and reduces the expression of cytokines such as IL-2 and IFN-γ, thereby achieving immunosuppression. Additionally, CsA regulates key immune regulatory factors such as STAT3, NFKB1, TGFB1, IL10, and FOXP3, promoting immune tolerance and regulatory T cell (Treg) function.
Psoriasis is a chronic inflammatory skin disease. CsA alleviates skin inflammation and keratosis by inhibiting signaling pathways such as RARA, RARG, STAT3, MAPK1, TNF, NOS2, MAPK8, ELANE, PIK3CA, and EGFR. CsA shows rapid and significant efficacy in the treatment of psoriasis, especially for moderate to severe cases.
CsA is a cornerstone drug in the field of organ transplantation. By inhibiting immune cell activation and migration mediated by IL-2, PPP3CA, cyclophilin A (PPIA), and integrin LFA-1 (CD11a/CD18), it significantly reduces the incidence of rejection and improves transplant organ survival rates. The immunosuppressive mechanisms of CsA have been extensively studied, providing a theoretical basis for clinical immune regulation.
Sjögren's Syndrome is an autoimmune disease characterized by inflammation of the exocrine glands. CsA reduces glandular inflammation and improves dryness symptoms by regulating targets such as PPP3CA, IL17A, B cell activator (TNFSF13B), and cyclophin A. Clinical studies have shown that CsA applied topically to the eye has good safety and efficacy.
The main mechanism of action of cyclosporin A is based on its high affinity for intracellular cyclophinin A (PPIA), forming the CsA-PPIA complex. This complex specifically inhibits calcineurin (PPP3CA), blocks NFAT dephosphorylation, inhibits NFAT transcription factor entry into the nucleus, and reduces the transcriptional expression of pro-inflammatory cytokines. This mechanism is at the core of CsA's immunosuppressive effects.
Additionally, CsA can inhibit the adhesion and migration of immune cells mediated by integrin LFA-1 (CD11a/CD18), further weakening immune responses. CsA regulates multiple signaling pathways, including STAT3, NF-κB, and MAPK, involving cell proliferation, apoptosis, and the regulation of inflammatory responses.
In rheumatoid arthritis, CsA inhibits inflammatory cell activation and joint destruction by regulating targets such as AMPK, BCL2, NOTCH1, and TLR4. In psoriasis, CsA affects signaling pathways such as RARA, RARG, and PI3K/AKT, alleviating skin inflammation. In Sjögren's syndrome, CsA regulates IL17A and B cell activating factors, reducing gland inflammation.
Overall, CsA achieves broad immunomodulatory and anti-inflammatory effects through multi-target and multi-pathway synergistic effects.
Cyclosporin A has a relatively large molecular weight (1202.61 Da) and high polarity and a number of hydrogen bond receptors, resulting in low oral bioavailability at about 20%. CsA has moderate lipid solubility (LogP=3.5), which aids cell membrane penetration, but its higher TPSA and molecular weight limit passage through the blood-brain barrier, resulting in lower concentrations in the brain.
CsA has a half-life of about 8 hours and a relatively long retention time in the body, making it suitable for routine administration. Its main metabolic pathway is metabolism mediated by the hepatic cytochrome P450 enzyme system (especially CYP3A4), with most metabolites excreted through bile. CsA has certain hepatotoxicity and requires monitoring liver function indicators to avoid liver damage caused by long-term high-dose use.
In terms of safety, CsA showed no significant cardiotoxicity or hERG channel inhibition, and the Ames-induced mutagenic test was negative, indicating a low genotoxicity risk. However, hepatotoxicity and nephrotoxicity of CsA require close clinical monitoring.
As a classic immunosuppressant, cyclosporine A has been widely used for the prevention and treatment of organ transplant rejection, significantly improving transplant success rates and patient quality of life. Its application in autoimmune diseases such as rheumatoid arthritis, psoriasis, and Sjögren's syndrome is also increasing, demonstrating good clinical efficacy.
In the future, with deeper understanding of CsA's mechanism of action and advances in drug delivery technology, clinical applications of CsA will become more precise and safe. New technologies such as nanocarriers and targeted delivery systems are expected to improve the bioavailability and tissue distribution of CsA, reducing toxic side effects. Additionally, the design and synthesis of derivatives based on the CsA structure may lead to the development of more selective and less toxic immunomodulators.
By combining multi-omics and systemic pharmacology approaches, in-depth analysis of CsA's multi-target network of action in different diseases will help optimize its clinical application and expand new indications. Especially its potential applications in immune-related tumors, autoimmune diseases, and inflammatory diseases warrant further exploration.
Cyclosporin A, a cyclic peptide immunosuppressant derived from natural fungi, plays an important role in immunoregulation due to its unique molecular structure and multi-target mechanism. Its widespread application in organ transplantation and various autoimmune diseases fully demonstrates the value of natural products in modern medicine. Despite certain hepatotoxicity and bioavailability limitations, with continuous advances in drug delivery technology and structural optimization, the clinical prospects for CsA and its derivatives remain broad. Future research should focus on improving its safety, targeting, and efficacy, providing more effective drug options for treating immune-related diseases.
Shenshuai
Wenjing
Hedandan
