Cyclosporin H is a naturally occurring chemical compound and a member of the cyclosporine family. These compounds are produced by the fungus Tolypocladium inflatum. While closely related to the well-known immunosuppressant drug, cyclosporin A, cyclosporin H itself lacks significant immunosuppressive activity.
The Cyclosporine Family
The cyclosporines are a group of cyclic peptides, which are ring-shaped molecules made of amino acids. The most recognized member of this group is cyclosporin A, a drug prescribed to prevent organ transplant rejection and treat autoimmune disorders due to its ability to suppress the immune system.
There are numerous other cyclosporines, designated by different letters such as B, C, D, and H. Each of these is a natural analogue, meaning they are structurally very similar with only minor variations. These differences arise from substitutions in the amino acid building blocks that make up the peptide ring. Cyclosporin H differs from cyclosporin A by a single amino acid at the eleventh position in its structure, an alteration that has profound consequences for its biological function.
Mechanism of Action
The immunosuppressive effects of cyclosporin A begin when it enters a cell and binds to an intracellular protein called cyclophilin. This newly formed cyclosporin A-cyclophilin complex then inhibits another protein, a phosphatase called calcineurin. The inhibition of calcineurin blocks a signaling pathway needed to activate T-cells, which is the direct cause of the immunosuppressive effect.
Cyclosporin H can also enter cells and bind to the same cyclophilin protein with high affinity. However, the resulting cyclosporin H-cyclophilin complex is functionally different, as it is unable to bind to or inhibit calcineurin.
This failure to inhibit calcineurin is why cyclosporin H lacks immunosuppressive properties. The single amino acid difference between the two molecules prevents the final step in the mechanism. It effectively occupies the cyclophilin binding site without triggering the subsequent immunosuppressive cascade.
Research and Therapeutic Potential
Cyclosporin H is a valuable tool in scientific research. Because it binds to cyclophilin but does not inhibit calcineurin, it serves as an experimental control to distinguish the effects of cyclophilin binding from those of calcineurin inhibition. By comparing the cellular outcomes of treatment with cyclosporin A versus cyclosporin H, researchers can isolate events specifically due to the suppression of calcineurin.
Beyond its use as a control, cyclosporin H has been investigated for other applications. One area of interest is its ability to inhibit P-glycoprotein, a transport protein that pumps chemotherapy drugs out of cells, leading to multidrug resistance in cancer. Blocking this pump could make cancer cells more sensitive to treatment.
Its activity as a selective antagonist for the formyl peptide receptor 1 (FPR-1) has also been noted. This receptor is involved in inflammatory responses, and by blocking it, cyclosporin H can inhibit certain inflammatory pathways. This has led to investigations into its potential as an anti-inflammatory agent.
Known Biological Effects and Safety Profile
The biological effects of cyclosporin H are understood from laboratory studies in cell cultures and animal models. Unlike cyclosporin A, which has well-documented side effects like kidney toxicity, cyclosporin H is considered immunologically inactive. Its safety profile is defined by this lack of immunosuppression, meaning it does not carry the same risks associated with weakening the immune system.
In laboratory settings, it has been shown to inhibit certain cellular processes. It can block the effects of tumor-promoting compounds in mouse skin and interfere with a calcium-dependent process involving protein synthesis. It has also been observed to enhance the efficiency of gene delivery into certain types of stem cells, a tool used in gene therapy research.