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℃
Cyclosporin A (CsA) is an immunosuppressive agent with significant clinical value, first isolated from the fungus Tolypocladium inflatum in the 1970s. CsA has become a milestone drug in the prevention and treatment of organ transplant rejection due to its unique immunomodulatory effects, especially its significant effects in inhibiting T cell activation and cytokine release. With the deepening of research, the potential application of CsA in autoimmune diseases such as rheumatoid arthritis, psoriasis, and Sjogren's syndrome is gradually being revealed. This article provides a systematic review of the chemical structure and physicochemical properties, sources and extraction, pharmacological activity, mechanism of action, pharmacological 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 undecyl peptide with the molecular formula C62H111N11O12 and a molecular weight of approximately 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 that it has moderate lipid solubility, which is beneficial for penetrating cell membranes but limits its water solubility. Its topological polar surface area (TPSA) is 226.75 Å ² and the number of hydrogen bond acceptors is 12, indicating strong polarity and hydrogen bonding ability, which has important implications for its binding to target proteins and pharmacokinetic properties.
The structural characteristics of CsA enable it to bind with cyclophilin A (PPIA) in cells with high affinity, forming a complex that inhibits the activity of protein phosphatase 2B (PP2B, also known as calcineurin). The IC50 of this inhibitory effect is approximately 7 nM, demonstrating extremely high potency. In addition, CsA can inhibit cell adhesion mediated by integrin LFA-1 (CD11a/CD18), further regulating the function of immune cells.
Cyclosporin A was initially produced by fermentation of the fungus Tolypocladium inflatum (formerly known as Trichoderma polysporum). This fungus belongs to the Ascomycota phylum and is capable of synthesizing CsA in specific culture media. The traditional production process mainly relies on fermentation technology, using solid-state or liquid fermentation processes to improve yield by optimizing cultivation conditions (such as carbon source, nitrogen source, pH, temperature, dissolved oxygen, etc.).
The extraction methods usually include filtration, solvent extraction, and purification of the fermentation broth. The commonly used solvents are organic solvents such as ethyl acetate and methanol. Purification steps often use techniques such as silica gel column chromatography and high-performance liquid chromatography (HPLC) to obtain high-purity CsA. In recent years, with the development of fermentation engineering and molecular biology technology, the yield and purity of CsA have been significantly improved through genetic engineering of bacterial strains and optimization of fermentation processes.
The core pharmacological effect of cyclosporine A is immunosuppression, mainly by inhibiting T cell-mediated immune responses. CsA can effectively block T cell receptor (TCR) signaling, inhibit the production of pro-inflammatory cytokines such as IL-2, and thereby weaken the proliferation and activation of immune cells. Its main indications include 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 regulating 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 cytokines, alleviate joint inflammation and tissue damage. Clinical studies have shown that it has certain therapeutic effects in improving RA symptoms and delaying the course of the disease.
CsA inhibits the activity of calcium regulated phosphatase (PPP3CA) by binding to cyclophilin, 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 immune suppression. In addition, CsA regulates key immune regulatory factors such as STAT3, NFKB1, TGFB1, IL10, FOXP3, promoting immune tolerance and regulating T cell (Treg) function.
Psoriasis is a chronic inflammatory skin disease, and CsA reduces skin inflammation and keratinization abnormalities by inhibiting signaling pathways such as RARA, RARG, STAT3, MAPK1, TNF, NOS2, MAPK8, ELANE, PIK3CA, EGFR, etc. CsA shows rapid and significant efficacy in the treatment of psoriasis, especially in moderate to severe cases.
CsA is a cornerstone drug in the field of organ transplantation. It significantly reduces the incidence of rejection and improves the survival rate of transplanted organs by inhibiting immune cell activation and migration mediated by IL-2, PPP3CA, cyclophilin A (PPIA), and integrin LFA-1 (CD11a/CD18). The immunosuppressive mechanism of CsA has been widely studied, providing a theoretical basis for clinical immune regulation.
Sj ö gren's Syndrome is an autoimmune disease characterized by exocrine glandular inflammation. CsA reduces glandular inflammation and improves dryness symptoms by regulating targets such as PPP3CA, IL17A, B cell activating factor (TNFSF13B), and cyclophilin A. Clinical studies have shown that local application of CsA in the eye has good safety and efficacy.
The main mechanism of action of cyclosporine A is based on its high affinity binding with intracellular cyclophilin A (PPIA), forming the CsA PPIA complex. This complex specifically inhibits calcium regulated phosphatase (PPP3CA), blocks the process of NFAT dephosphorylation, inhibits the entry of NFAT transcription factors into the nucleus, and reduces the transcriptional expression of pro-inflammatory cytokines. This mechanism is the core of CsA's immunosuppressive effect.
In addition, CsA can also inhibit the adhesion and migration of immune cells mediated by integrin LFA-1 (CD11a/CD18), further weakening the immune response. CsA has regulatory effects on multiple signaling pathways, including STAT3, NF - κ B, MAPK, etc., involving cell proliferation, apoptosis, and inflammation response regulation.
In rheumatoid arthritis, CsA inhibits inflammatory cell activation and joint destruction by regulating targets such as AMPK, BCL2, NOTCH1, TLR4, etc. In psoriasis, CsA affects signaling pathways such as RARA, RARG, and PI3K/AKT to alleviate skin inflammation. In Sjogren's syndrome, CsA regulates IL17A and B cell activating factor, reducing glandular inflammation.
Overall, CsA achieves its extensive immunomodulatory and anti-inflammatory effects through multi-target and multi pathway synergistic effects.
The molecular weight of cyclosporine A is relatively large (1202.61 Da), and it has a high polarity and hydrogen bond receptor number, resulting in a low oral bioavailability of about 20%. CsA has moderate lipid solubility (LogP=3.5), which helps to penetrate cell membranes, but its high TPSA and molecular weight limit its passage through the blood-brain barrier, resulting in lower concentrations in the brain.
The half-life of CsA is about 8 hours, with a relatively long retention time in the body, making it suitable for daily administration. Its main metabolic pathway is mediated by the liver's cytochrome P450 enzyme system (especially CYP3A4), and metabolites are mostly excreted through bile. CsA has certain hepatotoxicity, and liver function indicators need to be monitored to avoid long-term high-dose use that may cause liver damage.
In terms of safety, CsA has no significant cardiac toxicity or hERG channel inhibition effect, and the Ames mutagenicity test is negative, indicating a low risk of genotoxicity. However, the hepatotoxicity and nephrotoxicity of CsA require close clinical monitoring.
Cyclosporin A, as a classic immunosuppressant, has been widely used in the prevention and treatment of organ transplant rejection, significantly improving the success rate of transplantation and the quality of life of patients. Its application in autoimmune diseases such as rheumatoid arthritis, psoriasis, and Sjogren's syndrome is also increasing, showing good clinical efficacy.
In the future, with a deeper understanding of the mechanism of action of CsA and advances in drug delivery technology, the clinical application 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. In addition, the design and synthesis of derivatives based on CsA structure may lead to the development of more selective and less toxic immunomodulators.
Combining multi omics and systems pharmacology methods to deeply analyze the multi-target action network of CsA in different diseases will help optimize its clinical application plan and expand new indications. Especially in the potential applications of immune related tumors, autoimmune diseases, and inflammatory diseases, it is worth further exploration.
Cyclosporin A, as a cyclic peptide immunosuppressant derived from natural fungi, plays an important role in the field of immune regulation due to its unique molecular structure and multi-target mechanism of action. Its wide application in organ transplantation and various autoimmune diseases fully reflects the value of natural products in modern medicine. Despite certain liver toxicity and bioavailability limitations, the clinical prospects of CsA and its derivatives remain broad with the continuous advancement of drug delivery technology and structural optimization. Future research needs to focus on improving its safety, targeting, and efficacy, providing more effective drug options for the treatment of immune related diseases.
