Characterizing a small molecule of Streptococcus cristatus for HIV drug design

描述（由申请人提供）：在世界所有地区，HIV-1感染者的总人数持续增加。由于没有有效疫苗的前景，遏制艾滋病毒-1的传播依赖于预防传播的措施，治疗依赖于抗逆转录病毒疗法。然而，耐药性问题日益严重，有些人携带并传播对多种不同药物具有耐药性的病毒。因此，越来越多的人很少或没有选择新的治疗方法。这突出表明需要开发新的抗逆转录病毒药物。我们最近发现一种小分子cristatus Streptococcus CC5A （S. cristatus CC5A）能够上调APOBEC3G和APOBEC3F的表达并抑制HIV的复制。本提案的具体工作是表征这种小分子，并研究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 CC5A小分子通过上调APOBEC3G和APOBEC3F表达来增强先天免疫，可能是一种潜在的新型抗hiv候选药物。为了验证这一假设，我们提出以下具体目标。(1)鉴定cristatus CC5A促进A3F和A3G表达的小分子。(2)探索S. cristatus在CD4+ t细胞、巨噬细胞和树突状细胞等HIV原发靶细胞中上调APOBEC3抑制HIV复制或传播的可能性。(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一种新型抗艾滋病毒药物的小分子奠定基础。公共卫生相关性：人类免疫缺陷病毒（艾滋病毒）是艾滋病的病原体，艾滋病是一种毁灭性的大流行病，2007年估计有3320万人感染，约200万人死亡。这一建议的目标是表征一个小分子的非致病性口腔细菌，可以抑制HIV复制。该研究将为开发新型抗艾滋病药物提供有价值的信息，最终为抗击艾滋病毒/艾滋病提供新的武器。

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.