Tolypocladium inflatum

Cyclic peptide from 11 amino acids. Preparation by fermentation of Tolypocladium inflatum Gams with addition of DL-a-aminobutyric acid to the fermentation medium. Isolation by homogenization of mycelium, extraction with 90 % methanol and column chromatographic purification. 

The cyclosporins are a group of cyclic peptides produced by fungi such as Cylindrocarpon lucidum and Tolypocladium inflatum. These agents show a rather narrow range of antifungal activity, but high levels of immunosuppressive and anti-inflammatory activities. The main component from the culture extracts is cyclosporin A, but some 25 naturally occurring cyclosporins have been characterized. 

Cyclosporine A Cyclosporine A, [R-[R, R -(E)]]-cyclo-(L-alanyl-D-alanyl-iV-methyl-L-leucyl-iV-methyl-L-leucyl-A-methyl-L-valyl-3-hydroxy-iV,4-dimethyl-L-2-amino-6-octenoyl-L-a-aminobutyryl-A-methylglycyl-iV-methyl-L-leucyl-L-valyl-iV-methyl-L-leucine) (31.2.2), is extracted from a cultural liquid of products of the vital activity of the mushroom Tolypocladium inflatum [14-17], and which is also proposed to obtain synthetically [18-20]. 

Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum. Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground. 

Immunosuppressant produced as a metabolite by the fungus species Beauvaria nivea Gams Tolypocladium inflatum Gams ... 

TH Aarino, SN Agathos. Production of extracellular enzymes and cyclosporin by Tolypocladium inflatum and morphologically related fungi. Biotechnol Lett 11 759-764, 1989. 

R Traber, H Hoffmann, HR Loosli, MPonelle, A von Wartburg. Neue Cyclosporine aus Tolypocladium inflatum. Die Cyclosporine K-Z. Helv Chim Acta 70 13-36, 1987. 

R Zocher, T Nihira, E Paul, N Madry, H Peeters, K Kleinkauf, U Keller. Biosynthesis of cyclosporin A partial purification and properties of a multifunctional enzyme from Tolypocladium inflatum. Biochemistry 25 550-553, 1986. 

Voclosporin (ISA-247, R1524) 88 (Isotechnika) is being evaluated in a Phase III trial for the treatment of psoriasis,250 as well as a Phase III trial by Lux Biosciences as for the treatment of uveitis (coded as LX211, Luveniq ).251,252 In addition, voclosporin 88 has completed a Phase lib trial for the prevention of kidney graft rejection. Voclosporin 88253,254 is a slightly more potent but less toxic semi-synthetic derivative of the fungal-derived immunosuppressant cyclosporin A 89, which has the same mechanism of calcineurin inhibition. Cyclosporin A 89 was first isolated from Tolypocladium inflatum by workers at Sandoz and its structure was published in 1976.255,256... 

Cyclosporine is a macrolide antibiotic cyclopeptide with 11 amino acids. It inhibits cytokines (primarily interleukin-2) produced by T-cells in response to antigen exposure. Cyclosporin A can be biosynthesized from soil fungus Tolypocladium inflatum or synthetically manufactured. Hazardous combustion and decomposition products of this process include carbon monoxide, carbon dioxide, nitrogen oxide, hydrogen chloride gas, and phosgene. 

Hodge KT, Krasnoff SB, Humber RA. Tolypocladium inflatum is the anamorph of Cordyceps subsessilis. Mycologia 88 715-719, 1996. 

Type species Tolypocladium inflatum W. Gams, nom. cons. 

Grafe U, Ihn W, Schlegel B, Hofle G, Augustiniak H, Sandor P. Structure of ergokinin C, a new carboxysterol antifungal antibiotic from a Tolypocladium inflatum mutant. Pharmazie 46 613-614, 1991. 

The soilborne fungus Tolypocladium niveum, originally classified as Trichoderma polysporum and then Tolypocladium inflatum, was shown to produce antifungal metabolites with a narrow antifungal spectrum [178]. The metabolites, now collectively known as the cyclosporins [179], subsequently became better known because of their potent... 

FK506 (tacrolimus), a natural product of Streptomyces tukubaensis, is a 23-membered macrolide antibiotic that contains a unique hemiketal-masked, a,P-diketo amide moiety (Fig. 1) [1]. It has a mode of action and toxicity profile similar to those of cyclosporin A (CsA), an immunosuppressive cyclic undecapeptide produced by Tolypocladium inflatum (Fig. 1), which has been used clinically for two decades to prevent rejection on transplantation of organs, such as kidney, heart, liver, and bone marrow. The use of CsA has led to a remarkable increase of survival of all organ allografts and has fueled a dramatic increase in the number of kidney, liver, cardiac, and bone marrow transplants [2]. Thus, CsA has revolutionized transplantation surgery, both in terms of efficiency and quality of life of the patient. FK506 is said to be a more potent immunosuppressant than CsA and was approved for the treatment and prevention of kidney transplant rejection. 

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