Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

The Discovery and Properties of Caspofungin^®, an Antifungal Agent that Inhibits Fungal Glucan Synthesis

F. Peláez

Centro de Investigación Básica, Merck, Sharp & Dohme de España, S.A., Madrid, Spain

The development of new antifungal agents to fight against systemic fungal infections (mainly candidiasis and aspergillosis) is a real medical need, given the high mortality rates and the limitations of conventional treatments (amphotericin B and the azoles). These limitations include the toxicity of amphotericin B as well as the increasing appearance of resistance and lack of efficacy against some pathogens in the case of the azoles. These drugs target the synthesis of ergosterol (for the azoles) or the stability of the plasma membrane (for amphotericin B). It is clear that drugs with new modes of action are needed. Glucan synthesis represents a valid target for the development of new therapies. Glucan is a polysaccharide made of glucose units linked by b-(1,3) or b-(1,6) bonds, and is an essential component of fungal cell wall. The first antifungal drug targeting b-(1,3) glucan synthesis that has reached the market is caspofungin acetate (Caspofungin^®; Cancidas^®), a semisynthetic derivative of a fungal natural product, the pneumocandin B₀, produced by a fungus (Glarea lozoyensis) isolated from a water sample of a pond close to the Lozoya River (Madrid, Spain). The compound belongs to the echinocandin family of lipopeptides consisting of a cyclic hexapeptide N-acetylated with an aliphatic chain of variable length, which are inhibitors of glucan synthesis and therefore have antifungal activity. The discovery and properties of this compound, both in vitro and in vivo, in animal models and clinical trials, will be reviewed in this presentation. Caspofungin® is a potent inhibitor of the growth of Candida and Aspergillus species, and it has been shown to be highly efficacious and very well tolerated in clinical trials of both invasive aspergillosis and candidiasis.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com