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The antifungal activity of synthetic endothiopeptdides, i.e. NvaΨ [CSNH]-FMDP and LysΨ [CSNH]-NvaΨ [CSNH]-FMDP was studied in medium containing blood serum, against selected Candida strains; Candida albicans Gu4 (fluconazole sensitive), C. albicans Gu5 (fluconazole resistant), C. albicans ATCC 10231, Candida krusei DSM 6128 and Candidaparapsilosis DSM 5784. Although thiopeptide bonds in the tested peptides increased their stability in blood serum, their antifungal activity, however, drastically decreased in comparison with the peptides containing non-modified peptide bonds. Moreover, the inhibitory activity towards glucosamine-6-phosphate synthase of thionated synthetic analogue of FMDP was performed. The thiopeptdide bond also influenced its inhibitory properties against enzyme from C. albicans.
The edeines analogs were tested in several in vitro and in vivo assays using the mouse model, with edeine B (peptide W1) and cyclosporine A as reference compounds. The peptides displayed moderate, stimulatory effects on concanavalin A-induced (ConA-induced) splenocyte proliferation, whereas their effects on pokeweed mitogen-induced (PWM-induced) splenocyte proliferation were inhibitory. The peptides inhibited lipopolysacharide-induced (LPS-induced) tumor necrosis factor alpha production but had little effect on interleukin 6 production. In the model of the humoral immune response in vitro to sheep red blood cells, peptide 1 was distinctly stimulatory in the investigated concentrations (1-100 μg/ml), whereas peptides 3 and 4 only stimulated the number of antibody-forming cells at the highest concentration (100 μg/ml). In the model of the delayed type hypersensitivity in vivo to ovalbumin, the peptides were moderately suppressive (3 being the most active). The reference peptide W1 stimulated ConA-induced cell proliferation at 1–10 μg/ml but was inhibitory at 100 μg/ml. It also inhibited PWM-induced cell proliferation in a dose-dependent manner. This peptide had no effect on the humoral immune response in vitro or on cytokine production, but inhibited DTH reaction in vivo. The relationship between structure and activity, and a possible mode of action of the peptides, is discussed in this paper.
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