CARBOHYDRATE-BASED PEPTIDOMIMETICS TO PREVENT CANDIDIAS

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Cell surface carbohydrates (oligosaccharides) play significant roles in a wide range of cellular recognition events. The exquisite specificity of such interactions has led to development of several promising carbohydrate-based therapeutics. However, the high cost of synthesizing oligosaccharides has proven to be significant barrier to more wide-spread use of this approach. Moreover, In instances where a therapeutic is optimally delivered via a "gene therapy" approach, there is no direct way of delivering a carbohydrate based agent. There are several examples of molecular mimicry in which unrelated molecules share sufficient surface topology to be considered functional equivalents. Peptide mimetics of a carbohydrate structure have been identified, and these would be relatively inexpensive to produce and could be delivered in vivo by standard gene therapy approaches. Candida albicans Is an opportunistic fungus which can cause life-threatening infection, particularly among immunocompromised individuals. The virulence of this organism is related, in part, to Its ability to adhere to host tissue surfaces via the recognition carbohydrate structures which decorate the cell-surfaces of both fungus and host. The goal of this exploratory research grant proposal is to test the hypothesis that peptidomimetics of specific cell-surface carbohydrate structures can be used to reduce the level of the in vivo oral candidiasis which accompanies (experimental) salivary gland hypofunction. We will use two complementary approaches to generate the peptidomimetics; (1) combinatorial libraries will be screened for peptides which bind to either lectins or antibodies which recognize the oligosaccharide of interest; and (2) peptide sequence will be derived from antibody hypervariable region sequences of anti-ldiotypic antibodies prepared against appropriate anti-oligosaccharide antibodies. The secondary structure of each peptide will be experimentally determined and kinetic parameters which quantitatively describe the interaction of each peptide with its cognate lectin or antibody will be obtained. Mimetics which cause significant reduction of Candida adhesion to buccal epithelial cells in vitro will then be tested in a surgically desalivated rat model system used previously in our laboratories.