PORPHYRINS AS MICROBICIDES FOR PREVENTION OF STDS/HIV

该项目的长期目标是通过开发有效的局部杀微生物剂来减少性传播疾病的传播。这一多项目的努力将集中在局部阴道杀菌和杀病毒化合物的开发上，能够使用卟啉和金属卟啉化合物杀灭几种性病病原体，而不会引起宿主炎症。我们以前的工作已经表明这些化合物具有有效和广谱的抗菌活性，并利用新的细菌靶标，并且一些卟啉还具有针对HSV-1，HSV-2和HIV的有效的杀病毒活性。该提案旨在进一步研究我们有希望的初步结果，探索这些发现背后的基础科学，并为此类药物作为局部杀微生物剂/杀病毒剂的临床应用奠定基础。因此，提出了以下单独项目：在项目I中，Luigi Marzilli博士和Dabney狄克逊博士将合成、纯化和表征用于项目中生物学研究的卟啉和金属卟啉，并将通过生物物理和分析方法支持生物学研究。在项目2中，Igor Stojiljkovic博士和William Shafer博士将研究卟啉对临床分离的STD、N。淋病和H. ducreyi和通常栖息在阴道中的阴道微生物。将在体外和细胞培养中研究卟啉的活性谱。在项目3中，Amy Sears博士将研究卟啉作为抗单纯疱疹病毒（HSV-1和HSV-2）的杀病毒剂的功效和作用机制。在项目4中，Richard Compans博士将确定卟啉和金属卟啉化合物对感染性HIV-1和SIV病毒体的杀病毒活性，研究发现对HIV具有杀病毒作用的卟啉的作用机制，并确定可以检测到HIV的可能抗性变体的频率。与项目5合作，将确定杀病毒卟啉在粘膜攻击模型中对SIV感染的保护作用。在项目5中，Kenneth Gould博士将专注于项目1-4中开发的潜在药物的体内评价。它将评估所选药物的毒理学和药效学方面;将评估灵长类动物模型中对雄性抗SIV感染功效的影响。

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.