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

基本信息

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
项目类别：
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

项目摘要

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）：全球所有地区的HIV-1人数总数继续增加。由于没有有效的疫苗的前景，HIV-1的传播的遏制依赖于防止传播的措施，并依赖于抗逆转录病毒疗法。但是，耐药性越来越有问题，有些人携带和传播对许多不同药物具有抗性的病毒。因此，越来越多的人几乎没有或根本没有新的治疗剂的选择。这凸显了需要开发新的抗逆转录病毒药物的需求。我们最近发现，CRISTATUS CC5A链球菌（S. cristatus cc5a）的一小部分能够上调Apobec3g和Apobec3f表达并抑制HIV的复制。该建议的具体工作是表征这一小分子并检查小分子在新型抗HIV药物发展中的临床潜力。我们假设CC5A链球菌的小分子通过向上调节APOBEC3G和APOBEC3F表达增强了先天免疫，并且可能是潜在的新型抗HIV药物候选者。为了检验假设，我们提出了以下特定目的。（1）识别和表征促进A3F和A3G表达的Cristatus cc5a的小分子。（2）利用链球菌上调apobec3并抑制原发性HIV靶细胞中的HIV复制或传播的可能性，包括CD4+ T细胞，巨噬细胞和树突状细胞。（3）阐明小分子激活ApoBec3基因转录的机制。该提案的成功完成将为开发小分子开发新的抗HIV药物奠定基础。公共卫生相关性：人类免疫缺陷病毒（HIV）是艾滋病的病因，这是一种毁灭性的大流行病，2007年的估计为3320万人感染，死亡约为200万。该建议的目的是表征来自非致病性口服细菌的小分子，该分子可以抑制HIV复制。这项研究将产生有价值的信息，以开发新型抗AIDS药物，最终提供与艾滋病毒/艾滋病作斗争的新武器。