The long term objective of this Project is to develop protegrins as safe and effective chemoprotective barrier to protect women from the acquisition of HIV, gonorrhea, chlamydia, syphilis, herpes or trichomonas infection during sexual intercourse. Protegrins are recently discovered natural peptide antibiotics that were originally isolated from porcine leukocytes. They contain 16-18 amino acids, including 4 cysteine residues that form 2 intramolecular disulfide bonds. Unlike defensins, to which they show primary sequence homology, and many other antibiotic peptides of animal origin, the antimicrobial activity of protegrins is enhanced by the presence of physiological salt concentrations and serum. The relatively simple structure of protegrins makes them highly amenable to solid phase chemical synthesis, and synthetic and native protegrins show identical antimicrobial activity in vitro. Initial tests of these congeners revealed that they also possessed strong inactivating activity. Despite their unusually broad antimicrobial spectrum, protegrins were not cytotoxic towards mammalian fibroblasts, lymphocytes or macrophages, even when tested at concentrations of 50 mug/ml.
The Specific Aims are: 1) To design, synthesize and test protegrrins and protegrin congeners that can inactivate HIV and other STD agents of micromolar and sub-micromolar concentrations. 2) To ascertain how specific structural features of protegrins and their congeners contribute to their ability against these STD pathogens. 3) To determine how the structural features affect the interaction of protegrins with host factors, including their binding to serum proteins, the potentiation of their antimicrobial efficacy by factors present in normal serum, their resistance to host proteases, and their cytotoxicity (or lack thereof) and their interactions with normal vaginal flora, as exemplified by lactobacilli. 4) To determine the 3-dimensional structures of protegrins by 2-D NMR and X-ray crystallography.
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