Review: Anti-infectives Echinocandin lipopeptide antifungal agents: New agents and recent chemical modification studies

Abstract

The search for new and effective antifungal agents has been intensified by the increase in the incidence of opportunistic infections due to immunological diseases and aggressive immunosuppressive chemotherapy. Natural products have provided several novel leads in this field. Of these the echinocandin lipopeptides are of special interest due to their fungicidal properties and low toxicity. Their mode of action uniquely targets fungal cell wall biosynthesis by inhibiting the production of β-(1,3)-D-glucan, an essential cell wall component. Echinocandin B (ECB) consists of a cyclic hexapeptide whose N-terminus is acylated with linoleic acid. Other natural products of this class have closely related structures with some modification of the cyclic peptide and/or the N-acyl fatty acid chain. Although these natural products share excellent antifungal activity, especially against Candida albicans, and low toxicity, further improvements in therapeutic and solubility properties were sought through chemical modification. Major efforts have been ongoing at both Merck and Lilly in the quest for natural and semisynthetic echinocandin lipopeptides which will provide novel clinical candidates with a unique mode of action. This article describes the development of this class of compounds by reviewing both the primary and patent literature.