The overall goal of this proposal is to develop antimicrobial lipid compounds which can be used as a topical microbicide to prevent the spread of sexually transmitted diseases (STDs). At present the most commonly used compound to prevent the spread of STDs is the detergent nonoxynol-9, which can cause damage to mucosal tissues thereby facilitating the spread of STDs. Antimicrobial lipids occur naturally in human milk at mucosal surfaces. Lipid mixtures containing fatty acids, onoglyceride esters and monoglyceride ethers will be evaluated to determine whether they inactivate herpes viruses, chlamydia trachomatis and other sexually transmitted bacteria as well as the sexually transmitted protozoan Trichomonas vaginalis without substantially decreasing the intravaginal concentration of Lactobacillus. If some bacterial pathogens prove resistant to lipid inactivation, chelating agents such as sodium citrate will be used to increase lipid penetration in resistant gram negative bacterial membranes. In addition to designing mixtures of active lipid derivatives, lipid precursor molecules, which can be activated by lipases, phosphatases and other enzymes intravaginally, will be synthesized and tested for efficacy. Fatty acid derivatives with increased aqueous solubility, such as saccharide derivatives, will also be evaluated. Mucosal protective function consists of a number of protective factors which inactivate pathogens by different mechanisms. Preliminary studies showing that retinoic acid reduces herpes simplex virus-I (HSV-1) replication in epithelial cells will be continued with HSV-1 and HSV-2. As part of these studies all-trans-retinoic acid, 9-cis-retinoic acid and 13-cis-retinoic acid will be used to reduce herpes virus replication. To reduce potential retinoic acid toxicity and to increase aqueous solubility, retinoic acid derivatives such as retinoyl-beta-glucuronide will be synthesized and tested for its efficacy in slowing herpes virus replication. The use of retinoids in conjunction with fatty acid derivatives provides complimentary approaches, direct inactivation and inhibition of viral replication, for controlling STDs. The successful completion of these studies will result in the production of a lipid based vaginal microbicide which will fill a critical need for compounds capable of reducing the spread of STDs. This project contributes to the program by transferring novel antimicrobial lipid mixes to core laboratories for in vitro testing, and to a primate system for evaluation of toxicity and effectiveness.
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