Validation of Cdc68p as a novel antifungal target.
Candida albicans is the main cause of systemic fungal infections for which there is an urgent need for novel antifungal drugs. The CP (Cdc68p-Pob3p) complex, which is involved in transcription elongation, was evaluated as a putative antifungal target. In order to predict the consequences of inhibition of this complex, the largest CP subunit in Saccharomyces cerevisiae, Cdc68p, was the first novel target to be tested in GATE, a recently described, quantitative target inactivation system. Depletion of the cell's pool of Cdc68p led to rapid cell death. Subsequently, the C. albicans orthologue of CDC68, CaCDC68, was cloned. Attempts to disrupt both alleles were unsuccessful, thus suggesting an essential role of CaCDC68 in this fungus also. Furthermore, CDC68 was proven to be present in Neurospora crassa and Aspergillus nidulans, thus suggesting that the CP complex is widespread among fungi and could serve as a broad range antifungal target. Analysis of Cdc68p and Pob3p sequences indicated significant structural differences between fungal CP complexes and those present in higher eukaryotes. These results predict that, in principle, fungal-specific ligands of CP complexes could be identified that could subsequently serve as chemical starting points towards the development of new antifungal therapeutic agents.
Buurman
Ed T
ET
Anadys Pharmaceuticals Ltd., 9050 Camino Santa Fe, San Diego, CA 92121, USA. Ed.Buurman@astrazeneca.com
Jiang
Weidong
W
McCoy
Melissa
M
Averett
Devron R
DR
Thompson
Craig M
CM
Wobbe
C Richard
CR
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D019327:Copper Sulfate / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D005069:Evaluation Studies as Topic; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010802:Phylogeny; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D035602:Transcriptional Elongation Factors
D000935:Antifungal Agents; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; C071238:SPT16 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D019327:Copper Sulfate