Immunosuppression is a form of therapy that prevents the immune system of patients from acting against transplanted tissues and organs; without the availability of immunosuppressive drugs, the progresses made in modern medicine, in particular regarding kidney, heart and liver transplants, would be unthinkable. Furthermore, immunosuppressants are used to control severe manifestations of allergic and autoimmune related diseases. Many of these drugs specifically address certain biochemical pathways that are crucial for the functioning of human defense against alien organisms, such as pathogens, by selectively inhibiting the immunocompetent lymphocytes or signal transduction cascades that regulate the transcription of cytokines. For this reason, patients treated with immunosuppressants often have to be hospitalized and treated in parallel with antibiotics to prevent infection.
Some of the most important immunosuppressive drugs are natural products that are being produced biotechnologically by fermentation of bacteria and fungi. While tacrolimus and sirolimus are derived from actinobacteria and will accordingly not be treated here, cyclosporine (35) and mycophenolate mofetil (33) are fungal metabolites, and the present entry is therefore dedicated to these important molecules.
Mycophenolic acid (34) was the first antibiotic discovered and isolated in crystalline form from fungi, contrary to what is written elsewhere in the literature, where the penicillins are often regarded as the oldest natural antibiotics. Biogenetically, this compound is a meroterpenoid, produced by Penicillium species, including P. brevicompactum and P. roquefortii, and its biosynthesis has recently been elucidated in the latter species (Del-Cid et al. 2016). For various reasons, the compound never made it into clinical development as an antibacterial or antifungal agent (Bentley 2000; Bills and Gloer 2016). Ultimately, its utility as an immunosuppressant became evident, and it is now the active principle of several marketed drugs, such as Myfortic® and CellCept®. The compound selectively inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme that is crucial for the biosynthesis of guanosine nucleotides in mammalian cells. As this enzyme is more essential in the T- and B-lymphocytes than in other cell types, and its isoform in the lymphocytes is more sensitive to mycophenolic acid, the drug has a more potent cytostatic effect on lymphocytes than on other cell types, and thereby suppresses the immune system (Allison and Eugui 2000). Another secondary beneficial effect of mycophenolı´c acid is the depletion of tetrahydrobiopterin, which is a co-factor for the inducible nitric oxide synthase (iNOS). Consequently, the administration of mycophenolic acid prevents damage of tissues mediated by peroxynitrite. The drug is mainly being used to prevent organ rejection following transplants, as well as in the therapy of psoriasis (Epinette et al. 1987) and other immunological disorders.
Cyclosporine A (35) was first discovered as a mildy active antifungal antibiotic by Dreyfuss et al. (1996), who also gave the first hints as to its immunomodulatory activity. The compound is a nonribosomally biosynthesized peptide derived from fermentation of the ascomycete Tolypocladium inflatum, and its biosynthetic gene cluster was recently elucidated by Bushley et al. (2013). After years of intensive research, it was found that this cyclopeptide has a highly specific biochemical mode of action as it selectively binds to cyclophilin A. This protein is an inhibitor of calcineurin, which is responsible for activation of transcription of the cytokine, interleukine 2. If interleukine 2 is depleted, the immune response of the human body will be suppressed and rejection of transplants can be prevented (Green et al. 1981; Wiesinger and Borel 1980). Therefore, cyclosporine A has become the active ingredient of blockbuster drugs, such as Sandimmune®, Neoral® and Restasis®). In addition to organ transplants, such immunosuppressants can be very useful in the therapy of other diseases, including allergies and neurodegeneration. An example for the latter indication is the synthetic drug, fingolimod (Gilenya®). In this context, it is worthwhile to note that many fungal metabolites are highly useful in therapy because they show the opposite activities in biological systems, i.e., they boost the immune system and therefore increase the resistance against pathogens or even help to prevent cancer. Striking examples for such molecules are the β-glucanes and protein–polysaccharide complexes that are being treated elsewhere herein.