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.

全球艾滋病毒-1携带者的总人数继续增加。没有任何有效的前景 疫苗，治疗感染者，防止艾滋病毒从感染者传播给未感染者 变得越来越重要。能够影响系统免疫的共生细菌通常涉及到 预防病毒感染的第一道防线。有了这些知识，我们第一个发现了一组 与口腔共生菌链球菌相关的寡糖分子(称为CC5Ap) CriStatus CC5A，发现它增强了A3G/F和MX2的表达，并抑制了HIV-1的复制。 靶细胞，如单核细胞来源的树突状细胞(MD-DC)。我们假设CC5Ap可能作为一种 潜在的预防/治疗艾滋病毒/艾滋病的药物，基于其提高A3G/F和MX2水平的行动。 在这一应用中，我们建议通过以下三个具体目标来检验这一假设：(1)先导化合物 潜在抗HIV新药先导化合物的筛选及构效关系研究 发展。(2)探讨先导化合物抑制HIV-1复制的机制。(3)确定 使用人宫颈移植的先导化合物的抗病毒效力和细胞毒性。这项研究将提供 关于先导化合物可能成为开发抗艾滋病毒候选药物的重要信息- 1/艾滋病药物，协同作用针对艾滋病毒-1复制的早期和晚期。因为在临床上没有 批准的基于增强宿主天然免疫力的抗HIV-1药物，这项工作将促进开发一种 新一类HIV-1抗病毒药物。