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

本项目的目标是鉴定具有高杀灭病毒和杀菌广谱活性，并具有低毒性的人工卟啉药物，用于阴道内使用的局部杀微生物剂，以防止性病的传播。初步数据证实，几种卟啉是有希望的不依赖光的杀微生物剂，对STD中流行的病毒和细菌都有活性。该项目的主要目标是发现外围取代基(目标1)和金属中心(目标2)，它们的活性高于这些有希望的卟啉。我们将为其他项目提供分析/生物物理/机械支持，包括合成可用于提供这种支持的类似物所需的卟啉。人工卟啉药物，在这里设计为NPs和MNPs，可以基于天然的卟啉，但分别经过侧链或侧链和金属的修饰。相应的完全合成的、侧链与天然卟啉有很大不同的卟啉分别命名为SPS和MSPs。指导我们设计和选择MNPs作为广谱杀菌剂进一步开发的关键项目2假设是：“MNPs通过吸收血红素进入细菌。”“耐药菌株必然会减少铁的摄取，从而降低毒力。”项目3的初步结果表明，一些相同的MNPs强烈抑制HSV-2的传染性。HIV，项目4的焦点，被一些NPs抑制，但SPS和MSP更活跃。项目3和4的主要假设是“杀灭病毒的卟啉通过与感染所必需的病毒蛋白的特定分子相互作用而起作用。”由于性传播可能涉及无细胞或细胞相关病毒，因此可能需要几种在细胞穿透方面不同的卟啉来配制有效的局部杀菌剂。如HIV、HSV和细菌杀菌剂等活性卟啉的重叠结构特征为我们的综合评估程序提供了效率。我们研究的一个非常理想和现实的结果是鉴定出一种具有非常高的HSV/HIV病毒杀灭活性和非常高的杀菌活性的无毒制剂。鉴于初步和公布的活动数据，这是一个现实的目标，我们持乐观态度。然而，将几种或几种卟啉与其他类别的有希望的化合物结合在一起的局部杀微生物剂配方是一个潜在的未来方向。

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.