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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（由申请人提供）：艾滋病毒/艾滋病在人群中的持续传播主要是由于性接触受艾滋病毒污染的精液/精浆（SP）而加剧的。SP含有HIV感染性增强因子，其包括至少两种主要的天然存在的淀粉样蛋白原纤维，其促进病毒体附着于细胞靶。SP还含有多种促炎因子，其可通过促进细胞因子/趋化因子的产生间接促进HIV传播，所述细胞因子/趋化因子募集容许细胞、增强HIV穿过生殖器上皮的易位并激活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HIV杀微生物剂方面普遍缺乏成功。为了鉴定SP的HIV增强活性的抑制剂，我们进行了HIV增强SP淀粉样蛋白分解剂的小分子筛选。我们确定了四个命中，其中之一是没食子酸（GA），一种天然存在的化合物存在于葡萄籽中，以前曾报道过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SP和SP淀粉样蛋白增强HIV感染的能力。有趣的是，GA先前已被报道具有抗炎特性，包括抑制NF-kB信号传导的能力。总之，这些观察结果表明，GA可以通过双重靶向淀粉样蛋白和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种化合物命中抑制SP淀粉样蛋白活性的条件以及发生这种情况的机制（目的1），并确定GA是否抑制SP诱导的生殖器炎症，从而促进传播（目的2）。这些研究将揭示GA和其他化学分解剂是否是一种有前途的化合物，可以作为HIV杀微生物剂的一种成分进一步开发，并为SP增强HIV传播的多种机制提供见解。