Antifungal drug targets: Candida secreted aspartyl protease and fungal wall beta-glucan synthesis.
The incidence of severe, life-threatening fungal infections has increased dramatically over the last decade. Unfortunately, in practice the arsenal of antifungal drugs is limited to flucytosine, a few approved azoles, and polyenes, mainly amphotericin B. This situation is rather precarious in view of the extended spectrum of fungi causing severe disease in immunocompromised patients, development of resistance to some of the currently used agents, and the minimal fungicidal activity of the azoles. Although lagging behind the need for new antifungal agents, the study of fungal biochemistry, physiology, and genetics has undergone a resurgence to new heights of activity, thus providing a framework on which to build drug discovery programs in several new areas, two of which will be discussed in detail: the biology of Candida albicans secreted aspartyl protease with respect to inhibitor discovery, evaluation, and possible clinical utility; and the fungal cell wall beta-glucans with respect to the mechanism and regulation of synthesis and target sites for drug inhibition.
Goldman
R C
RC
Dept. 47M, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Frost
D J
DJ
Capobianco
J O
JO
Kadam
S
S
Rasmussen
R R
RR
Abad-Zapatero
C
C
D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D002176:Candida albicans / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D015195:Drug Design; D005260:Female; D005936:Glucans / Q000096:biosynthesis; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology; D029702:Schizosaccharomyces pombe Proteins; D014774:Virulence; D047071:beta-Glucans
D000935:Antifungal Agents; D005936:Glucans; D008565:Membrane Proteins; D011480:Protease Inhibitors; D029702:Schizosaccharomyces pombe Proteins; D047071:beta-Glucans; C033363:beta-1,3-glucan; D005964:Glucosyltransferases; C040232:glucan synthase; C020570:1,3-beta-glucan synthase; D016282:Aspartic Acid Endopeptidases; C086390:SAP1 protein, Candida albicans