Characterization of Gallic Acid as a Novel HIV Microbicide Candidate

没食子酸作为新型 HIV 杀菌剂候选物的表征

基本信息

批准号：
9096084
负责人：
Nadia R Roan
金额：
$ 19.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096084
关键词：
AIDS/HIV problem Affect Amyloid Amyloid Fibrils Anti-Inflammatory Agents Anti-inflammatory Biochemical Biological Assay Cells Chemicals Chemotaxis Enhancers Epithelial Epithelial Cells Epithelium Exposure to Female Gallic acid Genetic Transcription Genital system Grant HIV HIV Infections HIV-1 Health In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intention Investigation Mediating Microscopic Modeling NF-kappa B Nature Non-Steroidal Anti-Inflammatory Agents Peptides Predisposition Production Property Recruitment Activity Reporting Seminal Seminal Plasma Seminal fluid Signal Transduction Testing Transforming Growth Factor beta Viral Virion Virus Virus Diseases cell type cellular targeting chemokine conformer cytokine enhancing factor follow-up fundamental research grape seed inhibitor/antagonist insight microbicide monolayer nervous system disorder nonhuman primate novel novel strategies prevent reproductive tract response small molecule success tool transmission process vector transmission viral transmission

项目摘要

DESCRIPTION (provided by applicant): The continuing spread of HIV/AIDS in people is predominantly fueled by sexual exposure to HIV-contaminated semen/seminal plasma (SP). SP harbors HIV infectivity enhancing factors that include at least two major classes of naturally occurring amyloid fibrils that promote virion attachment to cellular targets. SP also harbors a variety of pro- inflammatory factors that can indirectly facilitate HIV transmission by promoting the production of cytokines/chemokines that recruit permissive cells, enhance the translocation of HIV across the genital epithelium, and activate HIV gene transcription. These direct and indirect HIV- enhancing effects of SP could help explain the general lack of success in developing a highly efficacious HIV microbicide. To identify inhibitors of SP's HIV-enhancing activity, we conducted a small molecule screen for disassemblers of HIV-enhancing SP amyloids. We identified four hits, one of which was gallic acid (GA), a naturally-occurring compound present in grape seeds that has previously been reported to inhibit fibril formation by amyloidogenic peptides associated with neurological diseases. We confirmed that GA inhibits the ability of both SP and SP amyloids to enhance HIV infection. Interestingly, GA has previously been reported to harbor anti-inflammatory properties, including the ability to inhibit NF-kB signaling. Together, these observations suggest that GA may inhibit SP-mediated enhancement of HIV infection by dually targeting the amyloids and the pro-inflammatory properties of SP. In this project, we characterize the conditions under which GA and the other 3 compound hits inhibit the activity of SP amyloids and the mechanisms by which this occurs (Aim 1), and determine whether GA inhibits SP-induced genital inflammation that can facilitate transmission (Aim 2). These studies will reveal whether GA and other chemical disassemblers would be a promising compound to develop further as a component of an HIV microbicide, and provide insights into the multiple mechanisms by which SP can enhance HIV transmission.

描述（由适用提供）：艾滋病毒/艾滋病在人们中的持续传播主要是由于性暴露于艾滋病毒污染的精液/精液等离子体（SP）的范围。 SP携带者HIV感染增强因素，包括至少两种主要发生的天然淀粉样蛋白原纤维，这些淀粉样蛋白原纤维促进了病毒附着在细胞靶标上。 SP还具有各种促炎性因素，可以通过促进细胞因子/趋化因子的产生来间接支持HIV传播，这些因子/趋化因子募集允许细胞，增强HIV在生殖器上皮中的易位，并激活HIV基因转录。 SP的这些直接和间接的HIV增强作用可以帮助解释在开发高效的HIV菌心方面总体上缺乏成功。为了鉴定SP增强艾滋病毒增强活性的抑制剂，我们进行了一个小分子筛选，以拆卸艾滋病毒增强的SP淀粉样蛋白。我们鉴定出四个命中，其中之一是食道酸（GA），这是一种天然存在的化合物，存在于葡萄种子中，以前据报道抑制与神经系统疾病相关的淀粉样蛋白生成肽的原纤维形成。我们证实GA抑制了SP和SP淀粉样蛋白增强HIV感染的能力。有趣的是，以前据报道GA具有抗炎特性，包括抑制NF-KB信号传导的能力。总之，这些观察结果表明，GA可以通过双向靶向淀粉样蛋白和Sp的促炎特性来抑制SP介导的HIV感染增强。在该项目中，我们表征了GA和其他3个复合命中的条件，抑制了SP淀粉样蛋白的活性以及发生这种情况的机制（AIM 1），并确定GA是否抑制了SP诱导的生殖器感染可以促进传播（AIM 2）。这些研究将揭示GA和其他化学拆卸器是否将成为进一步发展为HIV菌心成分的有望化合物，并提供有关SP可以增强HIV传播的多种机制的见解。