Technology offer: Cyclosporin derivatives for the treatment of asthma and rheumatoid arthritis

Cyclophilines are enzymes that help proteins in the human body to take on the right shape; only then can proteins fulfill their function in the cells. However, several of these “protein folding helpers” can also lead to inflammatory reactions in the body. Although previous therapies using cyclosporin inhibit inflammatory processes, they also severely weaken the immune system. At the Lead Discovery Center (LDC) and the Max Planck Research Unit for Enzymology of Protein Folding cyclosporin derivatives were developed which make it possible to address only disease-related cyclophilines and to inhibit them. Thereby the inflammation is inhibited without weakening the immune system. The new derivatives could thus represent a new treatment option for diseases such as asthma and rheumatoid arthritis (RA).CyclophilinPicture:  The enzyme cyclophilin

The cyclophilines move both within (intracellular) and between human cells in the extracellular space and act as folding helper enzymes. However, it is known that the activities of the extracellular cyclophilines can attract immune cells (chemotaxis) and thereby can lead to inflammatory processes in the body. Due to its anti-inflammatory properties, cyclosporin is currently being used for the treatment of such inflammations. This active ingredient, which belongs to the class of immunosuppressants, is widely used in transplantation medicine to prevent organ rejection. However, as a broad-spectrum agent, cyclosporin inhibits both activities of the extra- and intracellular cyclophilines and leads to an impairment of the entire immune system. New cyclosporin derivatives now allow the exclusive inhibition of extracellular cyclophilines. For this purpose, various components of the peptide cyclosporin were changed using biotechnological methods, which now prevent the entry into human cells. Therefore, the cell-impermeable derivative cannot attach itself to the intracellular cyclophilines, which are not responsible for the disease, thereby inhibiting their function. Subsequently, this indirectly prevents the inhibition of the enzyme calcineurin, which normally, when inhibited, would suppress the cellular immune system.

The LDC has already developed a series of lead structures, for which a proof of concept has already been designed. The novelty of these inhibitors is in their ability to exert their effect specifically in the extracellular space. Thus, the process of chemotaxis, in other words, the process whereby cells of the immune system (i.e. leukocytes) are attracted to the site of an inflammatory reaction, is stopped. This novel mechanism of action provides the basis for new drugs with few side effects that can be used in the treatment of asthma and rheumatoid arthritis.

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