The echinocandins: antifungals targeted to the fungal cell wall

Abstract

The greater incidence of AIDS and use of myelosuppressive therapy has increased the demand for effective antifungal therapy. Currently availiable therapy has limitations associated with toxicity and resistance potential. The ideal agent is selectively targeted to the fungal pathogen. The echinocandins, a family of cyclic lipopeptides, interfere with cell wall formation by noncompetitive inhibition of β-glucan synthase. Since mammalian cells lack a cell wall, this mode of action is likely responsible for the potent fungicidal activity and non-toxic properties of the echinocandin lipopeptides. New analogues of the echinocandins were prepared at the Lilly Laboratories by removal of the native fatty acid acyl group (“side chain”) from the cyclic peptide followed by its replacement with a new synthetic side chain. This scheme gave several analogues with improved therapeutic potential. A new analogue, LY303366, having a side chain containing a substituted terphenyl group, had improved potency against Candida albicans, Pneumocystis carinii, Histoplasma capsulatum and Aspergillus species, had oral bioavailability as well as an extended elimination half life. Newer developments in the discovery and modification of the pneumocandins by the Merck Laboratories are reported. New semi-synthetic water-soluble pneumocandin analogues L-705,589, L-731-373 and L-733,560 also have activity against disseminated aspergillosis.