Targeting HIV-1 Envelope glycoprotein incorporation

靶向 HIV-1 包膜糖蛋白掺入

• 批准号: 7685833
• 负责人: JUAN LAMA
• 金额: $ 21.84万
• 依托单位: RETROVIROX, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7685833
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adverse effects; Anti-HIV Therapy; Anti-Retroviral Agents; Antiviral Agents; Biological Assay; Biological Availability; Capsid; Cell Culture Techniques; Cell surface; Cell-Mediated Cytolysis; Cells; Defect; Development; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Future; Gagging; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human; Human Virus; Infection; Inhibitory Concentration 50; Intervention; Investigation; Knowledge; Lead; Libraries; Life Cycle Stages; Measures; Mediating; Molecular Weight; Monkeys; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Principal Investigator; Production; Property; Proteins; Reporter; Resistance; Screening procedure; Source; Specificity; Structure; Surface; System; T-Lymphocyte; Testing; Therapeutic Index; Time; Toxic effect; Viral; Virion; Virus; Virus Diseases; Work; antiretroviral therapy; base; cytotoxicity; drug discovery; efficacy testing; inhibitor/antagonist; macrophage; novel; novel strategies; pre-clinical; preconditioning; prevent; programs; public health relevance; receptor; research study; small molecule; small molecule libraries; success

DESCRIPTION (provided by applicant): Our most recent work identified a novel target for the development of anti-HIV therapies. We demonstrated that intracellular host monkey proteins prevent the incorporation of HIV-1 envelope (Env) glycoproteins into nascent virions. We obtained several lines of evidence that suggest that the monkey proteins preclude Env incorporation by interfering with HIV-1 Gag-Env interaction, a precondition for specific Env incorporation into budding virions. Most importantly, these virions, which lack Env, are noninfectious. Thus, Env incorporation represents a novel target for the development of new anti-HIV-1 agents. This observation is reminiscent of the CD4-mediated inhibition of Env incorporation into virions, which is also the subject of drug discovery efforts at Retrovirox. Importantly, we obtained evidence that the Env incorporation defect arises from the inability of Env to reach the cell surface. No drug targeting this critical step of the HIV life cycle is currently available. Moreover, to our knowledge, there has been no attempt to identify small compounds blocking Env cell surface expression and Env incorporation into virions. We recently screened a small number of compounds (1,500) for inhibitors of Env incorporation. This pilot experiment allowed us to identify a few hit compounds, which prevent Env incorporation without apparent toxicity to human cells. These findings demonstrate proof-of-concept that small molecules can block Env incorporation and render virions noninfectious, and make the project proposed here feasible. The objective of this phase I study is complete the screening of a larger library (20,000 compounds) using a specific and sensitive HIV-1 Env incorporation assay. Success in this Phase I application is defined as the milestone identification of at least 10 drug-like compounds with IC50s below 5 5M in HIV replication assays and minimal cytotoxicity (therapeutic index greater than 10). Lead compounds with these profiles will be optimized for potency, specificity and bioavailability in a Phase II project. This second proposal will aim at advancing the preclinical development of these compounds to support human trials. The specific aims of this proposal are: 1) Development of an HIV-1 Envelope incorporation assay, and; 2) Screening of small-molecule libraries. PUBLIC HEALTH RELEVANCE: As of the end of 2007, 33 million people worldwide are infected with HIV. Despite advances in antiretroviral therapies, side-effects and the emergence of viruses resistant to currently available drugs pose important problems for the treatment of HIV. We propose to identify and characterize antiretroviral compounds that block HIV through a novel mechanism. These unique compounds could be used for the treatment of HIV infection.

描述（由申请人提供）：我们的最新工作确定了抗HIV疗法发展的新目标。我们证明，细胞内宿主猴子蛋白可以阻止将HIV-1包膜（Env）糖蛋白掺入新生的病毒体中。我们获得了几条证据，表明猴子蛋白通过干扰HIV-1 GAG-ENV相互作用而排除了掺入，这是特定环境中的特定环境中的前提。最重要的是，这些缺乏ENV的病毒体是非感染的。因此，Embionation代表了新的抗HIV-1代理发展的新目标。这一观察结果让人联想到CD4介导的Embistion Incompation Inimporation纳入病毒体，这也是逆转录病毒的药物发现工作的主题。重要的是，我们获得的证据表明，环境缺陷是由于ENV无法到达细胞表面而产生的。目前没有针对艾滋病毒生命周期的关键步骤的药物。此外，据我们所知，没有尝试鉴定小型化合物阻断ENV细胞表面表达并置入病毒体中。最近，我们筛选了少量的化合物（1,500），以备环结合的抑制剂。该试验实验使我们能够鉴定出一些命中化合物，从而阻止了对人类细胞没有明显毒性的环境的掺入。这些发现证明了概念证明，小分子可以阻止环境并使病毒体非感染，并使此处提出的项目可行。该阶段I研究的目的是使用特定且敏感的HIV-1环境分析的较大库（20,000种化合物）完成筛选。在这一阶段的I施加中的成功定义为在HIV复制分析中至少10种具有IC50s的药物样化合物的里程碑鉴定和最小的细胞毒性（治疗指数大于10）。这些配置文件的铅化合物将在II期项目中优化，以实现效力，特异性和生物利用度。这第二个建议将旨在推进这些化合物的临床前发展，以支持人类试验。该提案的具体目的是：1）开发HIV-1信封掺入分析，以及； 2）筛选小分子库。公共卫生相关性：截至2007年底，全球3,300万人感染了艾滋病毒。尽管抗逆转录病毒疗法的进展，副作用和抗性病毒的出现在当前可用的药物方面对HIV的治疗构成了重要问题。我们建议识别和表征通过新机制阻断HIV的抗逆转录病毒化合物。这些独特的化合物可用于治疗HIV感染。