Characterizing a small molecule of Streptococcus cristatus for HIV drug design

表征用于 HIV 药物设计的冠状链球菌小分子

• 批准号: 9348881
• 负责人: Bindong Liu
• 金额: $ 32.74万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-08 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348881
• 关键词: AIDS/HIV problem; APOCEC3G gene; Acquired Immunodeficiency Syndrome; Adherence; Adverse drug effect; Anti-HIV Agents; Antiviral Agents; Biological Assay; Biology; Carbon; Cell Wall; Cells; Cervical; Cervix Uteri; Cessation of life; Chemicals; Clinical; Data; Dendritic Cells; Development; Disaccharides; Drug Design; Drug resistance; Foundations; Funding; Goals; HIV; HIV-1; Human; Immunity; Individual; Infection; Innate Immune System; Institutes; Intervention; Knowledge; Lead; Mass Spectrum Analysis; Multi-Drug Resistance; Mutation; Myxovirus; Natural Immunity; Oligosaccharides; Patients; Pharmaceutical Preparations; Pharmacology; Polysaccharides; Research; Resistance; Role; Streptococcus cristatus; T-Lymphocyte; Testing; Time; Vaccines; Vagina; Viral; Viremia; Virus Diseases; Virus Replication; Work; base; cellular targeting; chemical synthesis; commensal microbes; cytotoxicity; drug development; experimental study; innovation; irritation; monocyte; novel; oral bacteria; oral commensal; pandemic disease; prevent; screening; small molecule; transmission process; viral transmission; weapons

The overall number of people living with HIV-1 continues to increase worldwide. With no prospect for an effective vaccine, treating infected individuals and preventing HIV transmission from infected to uninfected individuals becomes increasingly important. Commensal bacteria that can impact systemic immunity are often involved as the first defense against viral infections. Given this knowledge, we were the first to identify a group of oligosaccharide molecules (termed CC5Ap) associated with the oral commensal bacterium Streptococcus cristatus CC5A, and found that it enhanced the expression of A3G/F and MX2, and inhibited HIV-1 replication in target cells, such as monocyte-derived dendritic cells (MD-DC). We hypothesize that CC5Ap may serve as a potential agent to prevent/treat HIV/AIDS based on its actions toward increasing the levels of A3G/F and MX2. In this application, we propose to test this hypothesis by the following three specific aims: (1) Lead compound screening and structural activity relationship (SAR) study of the lead compound for potential novel anti-HIV drug development. (2) Explore the mechanism of the lead compound in inhibiting HIV-1 replication. (3) Determine the antiviral potency and cytotoxicity of the lead compound using human cervical explants. This study will provide vital information regarding the potential of the lead compound to be a candidate for developing an anti-HIV- 1/AIDS drug, which synergistically targets both early and late stages of HIV-1 replication. As there is no clinically approved anti-HIV-1 drug based on boosting host innate immunity, this work will facilitate the development of a new class of HIV-1 antivirals.

HIV-1居住的人数的总数继续在全球范围内增加。没有有效的前景 疫苗，治疗受感染的个体并防止艾滋病毒传播向未感染的个体感染 变得越来越重要。可能影响全身免疫力的共生细菌通常涉及 首次防御病毒感染。鉴于这些知识，我们是第一个确定一组的人 寡糖分子（称为CC5AP）与口服共生细菌相关的链球菌 Cristatus cc5a，发现它增强了A3G/F和MX2的表达，并抑制了HIV-1复制 靶细胞，例如单核细胞衍生的树突状细胞（MD-DC）。我们假设CC5AP可以用作 基于其对增加A3G/F和MX2水平的行动预防/治疗艾滋病毒/艾滋病的潜在药物。 在此应用中，我们建议通过以下三个特定目的检验该假设：（1）铅化合物 潜在的新型抗HIV药物的铅化合物的筛查和结构活动关系（SAR）研究 发展。 （2）探索铅化合物在抑制HIV-1复制中的机制。 （3）确定 使用人宫颈外植体的铅化合物的抗病毒效力和细胞毒性。这项研究将提供 有关铅化合物的潜力是发展抗HIV的候选者的重要信息 1/AIDS药物，该药物协同靶向HIV-1复制的早期和晚期。因为没有临床 基于增强宿主先天免疫的批准的抗HIV-1药物，这项工作将有助于发展 新的HIV-1抗病毒药。