Sordarin antifungal agents

Abstract

Sordarins are natural products from a range of different producer fungi that show antifungal activity. Results from studies with a series of semi-synthetic sordarin derivatives from Glaxo Wellcome indicates the molecules show potential for broad spectrum activity, with a high antifungal specificity based on the nature of their interaction with protein elongation factor 2. Several of the compounds have demonstrated efficacy by sc. or oral administration in mouse models of Candida albicans, Histoplasma capsulatum, Coccidioides immitis and Pneumocystis carinii infection and early toxicological studies show no serious potential for adverse effects. However, the t_½ of the compounds in several animal species is very short, suggesting that high and repeated dosing may prove to be necessary for management of some serious fungal diseases. Patents for sordarin antifungals and for their target have been published principally from Glaxo Wellcome and from Merck & Co. However, Glaxo Wellcome has now terminated their own development programme for the agents and no details are yet available to indicate a candidate for clinical development will soon appear from Merck. The sordarins offer interesting potential thanks to the novelty of their mode of action; they may require substantially more research to reveal an ideal candidate for clinical development.

• antifungals
• azasorardins
• elongation factor 2
• sordarins