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(STDS)的传播。这一多项目的努力将集中在开发局部阴道杀菌和杀病毒化合物，能够灭活几种性传播疾病病原体，并使用卟啉和金属卟啉化合物不会在宿主中引起炎症。我们以前的工作表明，这些化合物具有强大的广谱抗菌活性，并利用了一个新的细菌靶点，一些卟啉类化合物对单纯疱疹病毒L、单纯疱疹病毒2型和人类免疫缺陷病毒也有很强的杀灭病毒活性。这项建议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，并为这类药物作为局部杀微生物剂/病毒剂的临床应用奠定基础。因此，提出了以下个别项目：在项目I中，Luigi Marzilli博士和Dabney Dixon博士将在项目中合成、提纯和表征用于生物学研究的卟啉和金属卟啉，并将用生物物理和分析方法支持生物学研究。在项目2中，伊戈尔·斯托基尔科维奇博士和威廉·谢弗博士将研究卟啉对性传播疾病、淋病奈瑟菌和杜氏杆菌临床分离株以及通常存在于阴道的共生生物的活性谱。活性的卟啉光谱将在体外和细胞培养中进行研究。在项目3中，艾米·西尔斯博士将研究作为杀病毒药物的卟啉对单纯疱疹病毒(单纯疱疹病毒L和单纯疱疹病毒2)的疗效和作用机制。在项目4中，Richard Compans博士将确定卟啉和金属卟啉化合物对传染性艾滋病毒-L和SIV病毒粒子的杀灭病毒活性，研究被发现对艾滋病毒具有病毒杀灭作用的卟啉的作用机制，并确定检测到艾滋病毒可能的抗药性变异的频率。与项目5合作，将在黏膜攻击模型中确定杀毒卟啉对SIV感染的保护作用。在项目5中，肯尼斯·古尔德博士将专注于对项目1-4中开发的预期药物进行体内评估。它将评估选定药物的毒理学和药效学方面；将在灵长类动物模型中评估对男性对抗SIV感染的效果。

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.