Fungal infections are responsible for a large portion of opportunistic infections in compromised hosts. Among the fungi, Candida albicans is one of the most prevalent agents causing secondary disease in patients weakened by cancer, immunosuppressive therapy, radiation treatment, and other debilitating conditions such as acquired immunodeficiency syndrome (AIDS). The currently used anticandidal drugs suffer from significant clinical limitations. We propose to take advantage of the biochemical difference between the cell envelopes of Candida and mammalian tissue to design drugs specific for this pathogenic yeast. In particular, we will adapt the polyoxins for use against medically important fungi. Since polyoxins are non-toxic to mammals and inhibit chitan synthetase, an enzyme essential for cell wall biosynthesis in fungi and invertebrates but absent from mammals, our drugs will be pathogen specific. Synthetic analogs of polyoxin L previously prepared in our laboratory inhibit chitin synthetase from C. albicans at micromolar concentrations. These peptidyl nucleosides also kill this yeast at millimolar concentrations in culture. The quantitative difference between the in vitro and in vivo activity of the synthetic polyoxins is a consequence of the poor permeation by the compounds into yeast and their degradation by intracellular peptidases. We will overcome the instability of the synthetic polyoxins toward peptidases by preparing molecules containing N-alkyl amino acide residues, dehydroamino acids, or peptide bond analogs such as ester, phosphonamide, and aminoxy moieties. The poor permeation of the polyoxins will be overcome by the attachment of lipophilic groups and peptide carriers to parts of the drug not necessary for activity. All modifications will be based on structure-function relationships that we have defined for the peptide transport system and chitin synthetase of C. albicans. The synthetic polyoxins will be examined against chitin synthetase in vitro and for their ability to alter the morphology and growth of C. albicans in culture. Based on our in vitro results, an established mouse model system will be used to evaluate promising candidates. This project should provide insights into the biosynthesis of cell wall components in C. albicans and may yield drugs against a variety of fungal patheogens.
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