Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite.

Abstract

A potent immunosuppressive activity was found in the culture broth of the fungus Isaria sinclairii (ATCC 24400).The metabolite, ISP-I ((2JS,3^,4^)-(j&)-2-amino-3,4-dihydroxy-2-hydroxymethyl-14oxoeicos-6-enoic acid, myriocin = thermozymocidin) suppressed the proliferation of lymphocytes in mouse allogeneic mixed lymphocyte reaction, but had no effect on the growth of humantumor cell lines.It also suppressed the appearance of plaque-forming cells in response to sheep red blood cells and the generation of allo-reactive cytotoxic T lymphocytes in mice after intraperitoneal or oral administration.The metabolite was 10-to 100-fold more potent than cyclosporin A as an immunosuppressiveagent of the immuneresponse in vitro and in vivo, and appears to be a candidate for clinical application as a powerful immunosuppressant.The success of humanorgan transplantations is dependent upon the use of potent immunosuppressive drugs.Cyclosporin A (CsA)2), a fungal cyclic peptide, is one such drug with powerful immunosuppressive properties in experimental and clinical organ transplantations.Recently, FK-5063f4), a novel macrolide from Streptomyces tsukubaensis, was found to be 10-to 100-fold more potent than CsA as an immunosuppressantand is currently under clinical trial.These two compoundsappear to have very similar immunosuppressive properties, but higher doses of both compounds induce renal dysfunction and other side effects.Therefore, improved drugs for the prevention of graft rejection with fewer side effects are needed.CsA was initially isolated from Trichoderma polysporum5f6) (the producing fungus has since been redesignated as Tolypocladium inflatum).On the other hand, Fujita et al.7'8) isolated a cyclic depsipeptide named trichospolide as an antibiotic from a strain of T. polysporum (Link ex Pers) Rifi.A strain of Isaria also produces a similar cyclic depsipeptide9'10).Wetherefore thought it worthwhile to screen these fungi for the production of novel immunosuppressive agents.As a result of the screening, we have found strong activity in the culture broth of Isaria sinclairii (ATCC24400), which is the imperfect stage of Cordyceps sinclairii.Cordyceps is a genus of fungus which belongs to Hypocreaceae, in the family of Ascomycetes, and is parasitic on insects such as Lepidoptera adonata and so on.Cordyceps sinensis Sacc.(Chinese