The goal of this program is to develop safe and effective topical antimicrobial agents for intravaginal use that will block sexual and perinatal transmission of viral and bacterial pathogens. Focusing on human primary cell cultures, Project 1 will evaluate candidate compounds that block human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus types 1 and 2 (HSV-1 and HSV- 2) infection. Although cell tropism for HSV and HIV is quite different and both viruses bind unique receptors and co-receptors during the processes of attachment and penetration, both interact with a common cell surface component, heparan sulfate (HS) glycosaminoglycans (GAGs). Similarly, the bacterial STD pathogens, Chlamydia trachomatis and N. gonorrhoeae, which are the focus of studies in Project 2, interact with HS GAGs during bacterial invasion. The binding of microbes to cell surface HS can be competitively blocked by sulfated polysaccharides (SPS). We have successfully identified several SPS or sulfated polymers that inhibit HSV and HIV-1 infection and exhibit little or no cytotoxicity. In further studies, we will more extensively evaluate this class of compounds. This will involve defining the HS sequence required for HSV invasion of cells of the human female genital tract as this receptor is the target for this class of candidate antimicrobials. We will also evaluate novel classes of candidate antimicrobials which may block other steps in viral pathogenesis. Because compounds cannot be optimally evaluated using cell lines, which are transformed and differ markedly from in vivo conditions, we have established primary cell culture systems for evaluation of candidate compounds. Using these model culture systems, we propose to further evaluate SPS and related compounds, identify new compounds, and determine how these agents inhibit viral pathogens. Knowledge gained about the mechanism of antiviral activity will facilitate the selection of rational combinations of compounds with enhanced potency or limited toxicities. Taken together, results of these studies should lead to identification of promising novel agents for topical formulation for intravaginal use to prevent STDs.
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