NOVEL MICROBICIDES FOR HIV PREVENTION

用于预防艾滋病毒的新型杀菌剂

• 批准号: 6255759
• 负责人: RICHARD W COMPANS
• 金额: $ 6.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6255759
• 关键词: AIDS education /prevention; HIV infections; acid base balance; antiAIDS agent; drug screening /evaluation; gene mutation; human immunodeficiency virus 1; pharmacokinetics; porphyrins; simian immunodeficiency virus; tissue /cell culture

The long range goal of this project is to develop effective topical microbicides for prevention of sexually transmitted HIV infection. In the proposed studies we will determine the virucidal activity of a series of porphyrin and metalloporphyrin compounds against infectious HIV- l and SIV virions. Based on results of our initial studies, Project l will design additional novel porphyrin compounds which will be evaluated in this project for their virucidal activity vs. HIV virions. The kinetics of inactivation as well as the possible pH-dependence of the virucidal effect will be determined against several HIV- l isolates, including primary isolates of subtypes A, C, and E. which are epidemiologicaIly most likely to be involved in sexual transmission. We will also evaluate the ability of the active compounds to protect cell cultures against infection by HIV or SIV. We will investigate alternative possible mechanisms by which these compounds could inactivate virion infectivity, including binding to specific viral proteins, disruptive effects on the structural integrity of the virion, and effects on specific functional activates of viral proteins. Because HIV has a high mutation rate, sequence variation in structural proteins might conceivably confer resistance to a given compound, depending on its mechanism of action. If such resistant mutants are detected, we will map the genetic alteration which is responsible, and determine whether any viral variants which are found to exhibit resistance to a specific compound will also exhibit resistance to other virucidal porphyrin compounds with distinct structural features. In preliminary studies, we have demonstrated that cell-free SIV can initiate infection following inoculation into the genital tract of female rhesus macaques. Based on the results of assays for virucidal activity obtained in this project and studies of the effects of porphyrins upon reproductive physiology in Project 5, the virucidal porphyrins which are most effective in cell culture systems and have no undesirable effects on physiology of the reproductive tract will be used in a primate model to determine the ability of pretreatment of the genital tract with these compounds to confer protection against challenge with infectious, pathogenic SIV. Thus. the project will develop a novel class of rnicrobicidal compounds, which are also active against sexually transmitted bacteria and herpesvirus.

该项目的长期目标是开发有效的局部杀菌剂来预防性传播艾滋病毒感染。在拟议的研究中，我们将确定一系列卟啉和金属卟啉化合物针对感染性HIV-1和SIV病毒颗粒的杀病毒活性。根据我们初步研究的结果，项目 l 将设计其他新型卟啉化合物，将在该项目中评估其相对于 HIV 病毒粒子的杀病毒活性。灭活动力学以及杀病毒作​​用可能的pH依赖性将针对几种HIV-1分离株来确定，包括A、C和E亚型的初级分离株，其在流行病学上最有可能涉及性传播。我们还将评估活性化合物保护细胞培养物免受 HIV 或 SIV 感染的能力。我们将研究这些化合物灭活病毒粒子感染性的替代可能机制，包括与特定病毒蛋白结合、对病毒粒子结构完整性的破坏性影响以及对病毒蛋白特定功能激活的影响。由于 HIV 具有高突变率，结构蛋白的序列变异可能会赋予对特定化合物的抗性，具体取决于其作用机制。如果检测到此类抗性突变体，我们将绘制造成这种情况的遗传改变图谱，并确定发现对特定化合物表现出抗性的任何病毒变体是否也会表现出对具有不同结构特征的其他杀病毒卟啉化合物的抗性。在初步研究中，我们已经证明，无细胞 SIV 在接种到雌性恒河猴的生殖道后可以引发感染。根据本项目获得的杀病毒活性测定结果以及项目5中卟啉对生殖生理学影响的研究结果，在细胞培养系统中最有效且对生殖道生理学没有不良影响的杀病毒卟啉将可用于灵长类动物模型，以确定用这些化合物预处理生殖道以提供针对传染性、致病性 SIV 攻击的保护作用的能力。因此。该项目将开发一类新型抗菌化合物，该化合物也能有效对抗性传播细菌和疱疹病毒。