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。这个多项目的努力将集中于局部阴道杀菌和杀病毒化合物的开发，能够灭活几种性病病原体，而不会引起宿主的炎症，使用卟啉和金属卟啉化合物。我们之前的工作表明，这些化合物具有有效的广谱抗菌活性，并利用新的细菌靶点，并且一些卟啉也对HSV- 1， HSV-2和HIV具有有效的杀病毒活性。本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，并为这类药物作为局部杀微生物/杀病毒剂的临床应用奠定基础。因此，建议以下个别项目：在项目一中，博士。Luigi Marzilli和Dabney Dixon将在项目中为生物学研究合成、纯化和表征卟啉和金属卟啉，并将用生物物理和分析方法支持生物学研究。在项目2中，dr。Igor Stojiljkovic和William Shafer将研究卟啉对临床分离的性病、淋病奈瑟菌和杜克雷伊嗜血杆菌以及通常栖息在阴道内的共生生物的活性谱。卟啉活性谱将在体外和细胞培养中进行研究。在项目3中，Amy Sears博士将研究卟啉作为抗病毒剂对抗单纯疱疹病毒（HSV- 1和HSV-2）的功效和作用机制。在Project 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病毒粒子的杀病毒活性，研究被发现对HIV具有抗病毒作用的卟啉的作用机制，并确定检测到HIV可能耐药变体的频率。在与Project 5的合作中，将在粘膜攻毒模型中确定病毒卟啉对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中开发的前瞻性药物的体内评估。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雄性抗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.