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: 8521319
• 负责人: Bindong Liu
• 金额: $ 31.49万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521319
• 关键词: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Appointment; CD4 Positive T Lymphocytes; Cells; Clinical; Containment; Cytidine Deaminase; Data; Dendritic Cells; Development; Drug Design; Drug resistance; Epithelium; Faculty; Funding; Genes; Genetic Transcription; Goals; HIV; HIV-1; Health; Human; Individual; Journals; Lead; Left; Life; Manuscripts; Measures; Molecular; Natural Immunity; Oral; Organism; Pathway interactions; Pharmaceutical Preparations; Process; Production; Proteins; Publications; Research; Research Design; Research Methodology; Research Personnel; Research Project Grants; Resistance; Science; Series; Signal Pathway; Signal Transduction; Streptococcus cristatus; Testing; Therapeutic; Vaccines; Virion; Virus; Virus Replication; Work; antiretroviral therapy; base; career development; drug candidate; fighting; macrophage; medical schools; member; monocyte; notch protein; novel; novel therapeutics; oral bacteria; pandemic disease; prevent; response; small molecule; tooth surface; transmission process; vif Gene Products; weapons

DESCRIPTION (provided by applicant): The overall number of people living with HIV-1 has continued to increase in all regions of the world. With no prospect for an effective vaccine, containment of the spread of HIV-1 relies on measures to prevent transmission, and treatment relies on antiretroviral therapy. However, drug resistance is becoming increasingly problematic, with some individuals harboring and transmitting viruses that are resistant to a number of different drugs. Thus, an increasing number of people are left with little or no options for new therapeutics. This highlights the need for the development of new antiretroviral agents. We recently discovered that a small molecule of Streptococcus cristatus CC5A (S. cristatus CC5A) is able to up-regulate APOBEC3G and APOBEC3F expression and inhibit HIV replication. The specific effort of this proposal is to characterize this small molecule and to examine the clinical potential of the small molecule in development of novel anti-HIV drug. We hypothesize that the small molecule of S. cristatus CC5A enhances innate immunity through up- regulating APOBEC3G and APOBEC3F expression and could be a potential novel anti-HIV drug candidate. To test the hypothesis, we propose following specific aims. (1) To identify and characterize the small molecule of S. cristatus CC5A that promotes A3F and A3G expression. (2) To exploit the possibility of S. cristatus upregulating APOBEC3 and inhibiting HIV replication or transmission in primary HIV target cells, including CD4+ T-cells, macrophages and dendritic cells. (3) To elucidate the mechanism by which the small molecule activates APOBEC3 gene transcription. The successful completion of the proposal will lay the groundwork for developing the small molecule to a novel anti-HIV drug. PUBLIC HEALTH RELEVANCE: Human immunodeficiency virus (HIV) is the causative agent of AIDS, a devastating pandemic disease with a 2007 estimate of 33.2 million people infected and around 2 million dead. The goal of this proposal is to characterize a small molecule from non-pathogenic oral bacteria that can inhibit HIV replication. This study will yield valuable information for developing novel anti-AIDS drug, eventually providing new weapons to fight HIV/AIDS.

描述（由申请人提供）：世界所有地区的HIV-1感染者总数持续增加。由于没有研制有效疫苗的前景，遏制HIV-1的传播有赖于采取预防传播的措施，而治疗则有赖于抗逆转录病毒疗法。然而，耐药性正变得越来越成问题，一些人携带和传播对许多不同药物具有耐药性的病毒。因此，越来越多的人对新疗法的选择很少或没有选择。这突出表明需要开发新的抗逆转录病毒药物。我们最近发现冠状链球菌CC 5A（S. Cristatus CC 5A）能够上调APOBEC 3G和APOBEC 3F表达并抑制HIV复制。该提案的具体努力是表征这种小分子，并检查这种小分子在开发新型抗HIV药物中的临床潜力。我们推测S. Cristatus CC 5A通过上调APOBEC 3G和APOBEC 3F表达增强天然免疫，可能成为潜在的新型抗HIV药物候选者。为了验证这一假设，我们提出了以下具体目标。(1)鉴定和表征S. Cristatus CC 5A促进A3 F和A3 G表达。(2)利用S. Cristatus上调APOBEC 3并抑制HIV在原代HIV靶细胞中的复制或传播，包括CD 4 + T细胞、巨噬细胞和树突细胞。(3)阐明小分子激活APOBEC 3基因转录的机制。该提案的成功完成将为将小分子开发为新型抗艾滋病毒药物奠定基础。公共卫生关系：人类免疫缺陷病毒（HIV）是艾滋病的病原体，艾滋病是一种毁灭性的流行病，2007年估计有3320万人感染，约200万人死亡。该提案的目标是表征来自非致病性口腔细菌的可以抑制HIV复制的小分子。本研究将为开发新的抗艾滋病药物提供有价值的信息，最终为防治艾滋病提供新的武器。