PROTEGRIN DESIGN

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Our long term goal is to design protegrin peptides that will be used both as topical microbicides to prevent sexually transmitted diseases (STDs) and as topical therapeutics to remediate bacterial vaginosis (BV). The Specific Aims of this project are: 1. To design protegrin-like molecules that inactivate multiple STD agents and the bacteria associated with bacterial vaginosis, without affecting normal vaginal flora. 2. To determine how the beta-sheet and turn regions of protegrins contribute to these activities. 3. To learn how protegrins interact with factors relevant to their use as topical microbicides, including a) host proteins, peptides, peptides and cells; b) host and microbial proteases; c) nonoxynol-9 other surfactants. 4. To study the effects of protegrins on C. albicans a frequent vaginal opportunist. 5. To examine how protegrins assemble into dimers and oligomers, and ascertain if and how such assemble relates to their antimicrobial, cytotoxic and hemolytic properties. Protegrins are small, exceptionally potent, beta-sheet peptides that rapidly inactivate many microbes, including those responsible for most sexually transmitted bacterial infections. We will use solid-phase peptide synthesis and precise methods of antimicrobial testing to "fine tune" protegrins for future intravaginal application. Our intent is to develop protegrin-like peptides that do not affect vaginal lactobacilli (e.g., L. acidophilus and L. crispatus), but are highly active against C. albicans, STD bacteria, and the flora associated with bacterial vaginitis/vaginosis. We can obtain this constellation of properties by introducing one or two amino acid substitutions into protegrins with 15-18 residues and two intramolecular disulfide bonds. We plan to generate a relatively small number of additional protegrin variants and to test their activity against a panel of STD target organisms. Overall, these studies will facilitate the development of novel, peptide- containing topical microbicides that are designed specifically for intravaginal use. Given the prevalence and serious consequences of STDs, topical microbicides that can protect and empower women are urgently needed.