VIRUCIDAL AND BACTERICIDAL PORPHYRINS--SYNTHETIC, MOLECULAR, ANALYTICAL STUDIES

杀病毒和杀菌卟啉——合成、分子、分析研究

• 批准号: 6347245
• 负责人: LUIGI G. MARZILLI
• 金额: $ 6.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347245
• 关键词: analytical chemistry; antibacterial agents; antiviral agents; capillary electrophoresis; chemical structure; drug design /synthesis /production; herpes simplex virus 2; high performance liquid chromatography; human immunodeficiency virus; porphyrins; sexually transmitted diseases; topical drug application

This program project's goal is to identify artificial porphyrin drugs possessing high virucidal and bactericidal broad spectrum activity and possessing low toxicity for formulation in topical microbicides for intravaginal use to prevent transmission of STDs. Preliminary data establish several porphyrins to be promising light-independent microbicides active against both viruses and bacteria that are prevalent in STD. This project's main aims are the discovery of peripheral substituents (Aim 1) and metal centers (Aim 2) which enhance activity above that of these promising porphyrins. We will provide analytical/biophysical/ mechanistic support to other projects, including the synthesis of porphyrins needed as analogs useful in providing this support. Artificial porphyrin drugs, designed here as NPs and MNPs, can be based on natural porphyrins but with modifications of side chains or side chain and metal, respectively. The corresponding porphyrins derived totally synthetically and with side chains very different from natural porphyrins are designated SPs and MSPs, respectively. The key Project 2 hypotheses guiding our design and selection of MNPs for further development as broad spectrum bactericidal agents are: "MNPs enter bacteria via heme uptake pathways." and "Resistant strains of bacteria would have, of necessity, reduced iron uptake and thus low virulence." Preliminary results in Project 3 show that some of the same MNPs strongly inhibit infectivity of HSV-2. HIV, the focus of project 4, is inhibited by some NPs but SPs and MSPs are more active. The main Project 3 and 4 hypothesis is "Virucidal porphyrins act by specific molecular interactions with viral proteins essential for infection." Since sexual transmission potentially involves either cell-free or cell- associated virus, several porphyrins, differing in cell penetrations may be needed for the formulation of an effective topical rnicrobicide. Overlapping structural features of porphyrins active as HIV, HSV, and bacterial microbicides afford an efficiency in our synthetic evaluation procedures. A highly desirable, realistic outcome of our research would be the identification of one non-toxic agent with very high HSV/HIV virucidal activity and very high bactericidal activity. Given the preliminary and published activity data, this is a realistic goal and we are optimistic. However, a topical microbicide formulation combining several porphyrins or porphyrins with other classes of promising compounds is a potential future direction.

该计划项目的目标是鉴定具有高病毒性和杀菌性广谱活性的人造卟啉药物，并具有低毒性，可用于局部菌心剂中的制剂，用于防止性病的传播。 初步数据建立了几种卟啉，是对病毒和细菌在STD中普遍存在的有望的光独立的微生物。该项目的主要目的是发现外围取代基（AIM 1）和金属中心（AIM 2），从而增强了这些有前途的卟啉的活性。我们将为其他项目提供分析/生物物理/机械支持，包括将需要的卟啉合成作为提供此支持的类似物。在此设计为NP和MNP的人工卟啉药物可以基于天然卟啉，但分别具有侧链或侧链和金属的修饰。完全合成的相应卟啉，侧链与天然卟啉截然不同，分别指定为SPS和MSP。关键项目2假设指导我们的设计和MNP的选择，以进一步开发，因为广谱杀菌剂是：“ MNPS通过血红素摄取途径进入细菌。”和“细菌的抗性菌株必须降低铁的摄取，从而降低毒力。”项目3中的初步结果表明，一些相同的MNP强烈抑制了HSV-2的感染性。艾滋病毒是项目4的重点，受到一些NP的抑制，但SP和MSP更为活跃。主要项目3和4假设是“病毒性卟啉作用于特定的分子相互作用与对感染必不可少的病毒蛋白的相互作用”。由于性传播可能涉及无细胞或相关病毒，因此几种卟啉，因此制定有效的局部rincinrobicide可能需要不同的细胞穿透性。活跃的HIV，HSV和细菌杀菌剂的卟啉的重叠结构特征在我们的合成评估程序中具有效率。我们研究的高度理想，现实的结果将是鉴定一种具有非常高的HSV/HIV病毒活性和非常高的杀菌活性的无毒剂。鉴于初步和已发布的活动数据，这是一个现实的目标，我们很乐观。然而，将几种卟啉或卟啉与其他有前途的化合物结合的局部杀菌剂配方是一个潜在的未来方向。