Small-molecule inhibitors of HIV-induced receptor downmodulation

HIV 诱导的受体下调的小分子抑制剂

• 批准号: 8052156
• 负责人: JUAN LAMA
• 金额: $ 35.63万
• 依托单位: RETROVIROX, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052156
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse effects; Affect; Agreement; Anti-Retroviral Agents; Antiviral Agents; Antiviral Therapy; Biological Assay; Biological Availability; CD4 Antigens; California; Cells; Commit; Development; Family; Flow Cytometry; Foundations; Genes; HIV; HIV Infections; Health; Human; Human Virus; Infection; Inhibitory Concentration 50; Intervention; Laboratories; Lead; Legal patent; Letters; Libraries; Licensing; Marketing; Mediating; Methods; Morphologic artifacts; Multi-Drug Resistance; Oral; Pathogenesis; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phorbol Esters; Physiological; Principal Investigator; Production; Proteins; Protocols documentation; Research; Resistance; Rights; Sales; Screening procedure; Signal Transduction; Specificity; System; Testing; Therapeutic; Therapeutic Index; Universities; Validation; Viral; Virus; Virus Diseases; Virus Receptors; Work; antiretroviral therapy; base; biosafety level 2 facility; cytotoxicity; cytotoxicity test; drug discovery; drug resistant virus; improved; in vivo; inhibitor/antagonist; lead series; novel; novel strategies; particle; pre-clinical; programs; public health relevance; receptor; resistant strain; small molecule; small molecule libraries; success; virology

DESCRIPTION (provided by applicant): Multiple lines of evidence suggest that down-modulation of the viral receptor in HIV- infected cells is an essential function modulating pathogenesis in vivo. We have previously performed proof-of-concept studies demonstrating that interference with this function results in the production of non-infectious particles unable to replicate in permissive cells. Here we propose to screen a library of small molecules to identify inhibitors of CD4 down-modulation. We will use a simple screening assay that recapitulates physiological conditions and use natural target cells of infection. We propose the following aims: (1) to optimize an assay for CD4 down-modulation in HIV-infected PBMC; (2) to screen a library of 20,000 drug-like compounds, and; (3) to validate and characterize the potency, cytotoxicity and specificity of hits. Studies will be implemented to optimize screening conditions, reduce assay-to-assay variability and perform statistical analysis to set thresholds for hit identification. False positives and artifacts will be discriminated in secondary assays, and true hit compounds will be prioritized based on potency, specificity, and lack of cytotoxicity. Preliminary studies will be performed to validate the mechanism of action and test the compounds antiviral activity with laboratory adapted HIV strains and primary isolates. Success in this Phase I application is defined as the milestone identification of one or more bona fide lead series of drug-like compounds with IC50s below 5 5M in HIV replication assays and minimal cytotoxicity (CC50 10-fold greater than IC50). Lead compounds with these profiles will be optimized for potency, specificity and bioavailability in a Phase II project aimed at advancing the preclinical development of these compounds to support human trials. These studies will constitute the foundation of a drug discovery program that may result in the characterization of first-in-class drugs of a novel family of antiretrovirals. 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)：多条证据表明，HIV感染细胞中病毒受体的下调是体内调节发病机制的重要功能。我们之前已经进行了概念验证研究，证明干扰这一功能会导致产生不能在允许细胞中复制的非感染性颗粒。在这里，我们建议筛选一个小分子文库来识别CD4下调的抑制剂。我们将使用一种简单的筛选方法来概括生理条件，并使用天然的感染靶细胞。我们提出了以下目标：(1)优化HIV感染的PBMC中CD4下调的检测方法；(2)筛选20,000个类药物化合物的文库；(3)验证和表征HITS的效力、细胞毒性和特异性。将进行研究，以优化筛查条件，减少化验之间的变异性，并进行统计分析，以设定命中鉴定的阈值。假阳性和伪影将在二次检测中被区分，真正的命中化合物将基于效力、特异性和缺乏细胞毒性而被优先排序。将进行初步研究，以验证作用机制，并用实验室适应的艾滋病毒毒株和初级分离株测试这些化合物的抗病毒活性。这一第一阶段应用的成功被定义为里程碑式地鉴定了一个或多个真诚的先导系列类药物化合物，在艾滋病毒复制试验中IC50低于55M，并且细胞毒性最小(CC50是IC50的10倍)。具有这些特征的先导化合物将在第二阶段项目中针对效力、特异性和生物利用度进行优化，旨在推动这些化合物的临床前开发，以支持人体试验。这些研究将构成药物发现计划的基础，该计划可能导致表征一种新型抗逆转录病毒药物家族的一流药物。公共卫生相关性：截至2007年底，全世界有3300万人感染艾滋病毒。尽管抗逆转录病毒疗法取得了进展，但副作用和对现有药物产生抗药性的病毒的出现对艾滋病毒的治疗构成了重要问题。我们建议通过一种新的机制来鉴定和表征能够阻断HIV的抗逆转录病毒化合物。这些独特的化合物可以用于治疗艾滋病毒感染。