echinocandin-b and Disease-Models--Animal

The synthesis and biological properties of a novel water-soluble echinocandin-like lipopeptide, FR131535, are described. This compound displayed potent in vitro and in vivo antifungal activities. The hemolytic activity of FR901379 was reduced by replacing the acyl side chain. This compound showed good water-solubility, comparable to the natural product FR901379.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bronchogenic Cyst; Candida albicans; Candidiasis; Disease Models, Animal; Echinocandins; Female; Fungal Proteins; Glucosyltransferases; Hemolysis; Membrane Proteins; Mice; Mice, Nude; Peptides; Peptides, Cyclic; Pneumonia, Pneumocystis; Schizosaccharomyces pombe Proteins; Solubility

In the course of screening for antifungal antibiotics, we have discovered a novel series of lipopeptide compounds structurally related to, but highly superior to, echinocandin B in terms of their water solubility due to the presence of a sulfate residue. These compounds, WF11899s, WF738s, WF14573s, WF16616 and WF22210, and their derivatives have diversity in their nuclear structures and acyl side chains. The producing strains were classified into two groups, the Coleomycetes group and the Hyphomycetes group. Compound FK463, a derivative of WF11899A, is currently in Phase 3 clinical development as a novel antifungal antibiotic.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Candidiasis; Disease Models, Animal; Echinocandins; Fungal Proteins; Fungi; Glucosyltransferases; Humans; Membrane Proteins; Mice; Microbial Sensitivity Tests; Mitosporic Fungi; Peptides; Peptides, Cyclic; Schizosaccharomyces pombe Proteins

The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.

Topics: Acute Disease; Amines; Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Candida; Candidiasis, Vulvovaginal; Disease Models, Animal; Dose-Response Relationship, Drug; Echinocandins; Female; Fungal Proteins; Mice; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Proline; Solubility; Structure-Activity Relationship; Yeasts