Sexually transmitted diseases (STDs) are a global public health problem. New strategies are needed to combat the growing epidemic. A promising new approach is the development of topical microbicides - safe and effective, female-controlled products designed for intravaginal use and intended to prevent infection at the portal of entry. In this application we propose an integrated program for microbicide development involving three projects and two cores. The program will investigate three groups of carefully selected compounds to determine their in vitro and in vivo effectiveness against important STD pathogens, assess for pertinent toxic properties including genital tract immunotoxicity, and determine whether they are contraceptive. The compounds to be investigate include: (1) sulfated polysaccharides and polymers we have previously shown to be broadly active and essentially non-toxic; (2) a diverse collection of compounds with antimicrobial properties and a history of safe use in humans; and (3) a group of novel compounds not previously investigated as potential microbicides. In Project 1, Drs. Herold and Klotman will examine the in vitro anti-HSV and anti-HIV-1 activity and cytotoxicity of the compounds. This project will make use of primary human cells: vaginal, endocervical and ectocervical cells as well as macrophages and dendritic cells to investigate antiviral activity, mechanism of action and toxicity. In project 2, Dr. Cooper will determine the anti-chlamydial and anti-gonococcal activity of the compounds investigating mechanism of action and toxicity using the human fallopian tube organ culture model. Studies in Projects 1 and 2 will provide important information regarding the spectrum of activity, mechanism of action and cytotoxicity profiles. Based on these data, the most promising compounds will progress to evaluation in Project 3 (Dr. Stanberry), where mouse and guinea pig models of genital tract infection will be used to investigate in vivo activity against HSV and chlamydia. Studies will investigate effects of body fluids (blood or semen) and issues related to female to male STD transmission. Compounds that appear likely to enter clinical trials will be examined in Project 3 to determine whether they adversely effect innate immune responses important in protection of the female genital tract. Other studies in Projects 1 and 2 will isolate heparan sulfate glycosaminoglycans (GAGs) from human genital tract cells and chlamydial elementary bodies and investigate the role of specific GAGs in HSV and chlamydial binding to cells. Core A will provide administrative support. Core B (Dr. Zaneveld) will assess contraceptive and toxic properties (lactobacillus growth, rabbit vaginal irritation, and acute oral toxicity) and prepare formulations. This integrated program will identify and characterize promising microbicides and develop information on new compounds or approaches (GAGs) that will provide future areas for investigation.
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