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.
| Laster, Brenda H; Dixon, Dabney W; Novick, Sara et al. (2009) Photon activation therapy and brachytherapy. Brachytherapy 8:324-30 |
| Vzorov, Andrei N; Weidmann, Armin; Kozyr, Natalia L et al. (2007) Role of the long cytoplasmic domain of the SIV Env glycoprotein in early and late stages of infection. Retrovirology 4:94 |
| Vzorov, Andrei N; Bozja, Jadranka; Dixon, Dabney W et al. (2007) Parameters of inhibition of HIV-1 infection by small anionic microbicides. Antiviral Res 73:60-8 |
| Liu, Xinyan; Olczak, Teresa; Guo, Hwai-Chen et al. (2006) Identification of amino acid residues involved in heme binding and hemoprotein utilization in the Porphyromonas gingivalis heme receptor HmuR. Infect Immun 74:1222-32 |
| Dixon, Dabney W; Gill, Anila F; Giribabu, Lingamallu et al. (2005) Sulfonated naphthyl porphyrins as agents against HIV-1. J Inorg Biochem 99:813-21 |
| Vzorov, A N; Bhattacharyya, D; Marzilli, L G et al. (2005) Prevention of HIV-1 infection by platinum triazines. Antiviral Res 65:57-67 |
| Bozja, J; Yi, K; Shafer, W M et al. (2004) Porphyrin-based compounds exert antibacterial action against the sexually transmitted pathogens Neisseria gonorrhoeae and Haemophilus ducreyi. Int J Antimicrob Agents 24:578-84 |
| Chen, Ching-ju; Tobiason, Deborah M; Thomas, Christopher E et al. (2004) A mutant form of the Neisseria gonorrhoeae pilus secretin protein PilQ allows increased entry of heme and antimicrobial compounds. J Bacteriol 186:730-9 |
| Chen, Xi-Juan; Seth, Shaguna; Yue, Gang et al. (2004) Influenza virus inhibits ENaC and lung fluid clearance. Am J Physiol Lung Cell Mol Physiol 287:L366-73 |
| Perkins-Balding, Donna; Ratliff-Griffin, Melanie; Stojiljkovic, Igor (2004) Iron transport systems in Neisseria meningitidis. Microbiol Mol Biol Rev 68:154-71 |
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