PORPHYRINS AS MICROBICIDES FOR PREVENTION OF STDS/HIV

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The long term goal of this project is to reduce the transmission of sexually transmitted diseases (STDs) by the development of effective topical microbicides. This multiproject effort will focus on development of topical vaginal bactericidal and virucidal compounds, able to inactivate several STD pathogens and not cause inflammation in the host, using porphyrin and metalloporphyrin compounds. Our previous work has shown these compounds to possess potent and broad-spectrum antibacterial activity and to utilize a novel bacterial target, and that some porphyrinss also have potent virucidal activity against HSV- l, HSV-2 and HIV. This proposal is designed to further investigate our promising initial results, to explore the fundamental science underlying these discoveries, and to lay the foundation for the clinical application of this drug class as topical microbicides/ virucides. The following individual projects are therefore proposed: In Project I Drs. Luigi Marzilli and Dabney Dixon will synthesize, purify, and characterize porphyrins and metalloporphyrins for biological studies in projects and will support the biological studies with biophysical and analytical methods. In Project 2, Drs. Igor Stojiljkovic and William Shafer will investigate the spectrum of activity of porphyrins against clinical isolates of STDs, N. gonorrhoeae and H. ducreyi and commensal organisms that would normally inhabit the vagina. The porphyrin spectrum of activity will be studied in vitro and in cell culture. In Project 3, Dr. Amy Sears will investigate the efficacy and mechanism of action of porphyrins as virucida1 agents against herpes simplex viruses (HSV- l and HSV-2). In Project 4, Dr. Richard Compans will determine the virucidal activity of porphyrin and metalloporphyrin compounds against infectious HIV- l and SIV virions, investigate the mechanism of action of the porphyrins found to be virucidal against HIV, and determine the frequency at which possible resistant variants of HIV can be detected. In collaboration with Project 5, the protective effect of virucidal porphyrins against SIV infection in a mucosal challenge model will be determined. In Project 5, Dr. Kenneth Gould will focus on in vivo evaluation of prospective drugs developed in projects 1-4. It will evaluate aspects of the toxicology and pharmacodynamics of selected drugs; will evaluate effects on male efficacy against SIV infection in a primate model.