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A Competition Binding Assay for Identifying Novel HIV-1 Capsid Ligands

用于识别新型 HIV-1 衣壳配体的竞争结合测定

基本信息

批准号：
8790352
负责人：
Christopher R Aiken
金额：
$ 35.29万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8790352
关键词：
AIDS/HIV problem Adherence Affinity Amino Acid Substitution Anti-Retroviral Agents Antiviral Agents Binding Binding Sites Biological Assay Calorimetry Capsid Capsid Proteins Cell Proliferation Cell Survival Chemicals Clinical Cytotoxic T-Lymphocytes Development Drug Targeting Epidemic Epitopes Exhibits HIV HIV therapy HIV-1 In Vitro Individual Infection Knowledge Lead Libraries Life Life Cycle Stages Ligands Measures Noise Pharmacologic Substance Pharmacotherapy Play Proteins Public Health Reading Recombinants Reporter Research Resistance Role Series Signal Transduction Staging Testing Therapeutic Titrations Viral Viral Drug Resistance Virus Work assay development base crosslink cytotoxicity effective therapy high throughput screening inhibitor/antagonist mutant novel public health relevance resistance mutation response scaffold scale up screening small molecule viral resistance

项目摘要

DESCRIPTION: HIV/AIDS remains a global epidemic and public health threat. Despite the development of effective antiretroviral drugs, therapy is not curative and is therefore life-long. Long-term therapy is often compromised by viral drug resistance mutations and incomplete adherence. The HIV-1 capsid represents an attractive target for therapy, though currently available inhibitors lack sufficient potency for clinical development. This project will develop a competition-based assay for small molecules targeting a specific pocket in the HIV-1 capsid and will adapt the assay for high-throughput screening of large compound libraries. The assay will be validated by screening a library of 10,000 small molecules and analyzing the hits for antiviral activity and cytotoxicity. This work will facilitate the identification of lead compounds for development of antivirals targeting the HIV-1 capsid, and will identify novel probes for HIV-1 capsid function. Specific Aims: Aim 1. Establish a competition-based high-throughput screening assay for small molecules that bind the H3-H4 pocket in HIV-1 CA. Aim 2. Perform pilot screens to validate the assay. Aim 3. Test the confirmed hits for antiviral activity against wild type HIV- and mutant viruses that are resistant to known capsid inhibitors.

描述：艾滋病毒/艾滋病仍然是一种全球流行病和公共卫生威胁。尽管开发了有效的抗逆转录病毒药物，但治疗并不能治愈，因此是终生的。长期治疗常常因病毒耐药突变和不完全依从性而受到影响。尽管目前可用的抑制剂缺乏足够的临床开发效力，但 HIV-1 衣壳代表了一个有吸引力的治疗靶点。该项目将开发一种基于竞争的检测方法，用于针对 HIV-1 衣壳中特定口袋的小分子，并将调整该检测方法以用于大型化合物库的高通量筛选。该检测方法将通过筛选 10,000 个小分子库并分析其抗病毒活性和细胞毒性来进行验证。这项工作将有助于鉴定用于开发针对 HIV-1 衣壳的抗病毒药物的先导化合物，并将鉴定用于 HIV-1 衣壳功能的新型探针。具体目标：目标 1. 针对结合 HIV-1 CA 中 H3-H4 口袋的小分子建立基于竞争的高通量筛选试验。目标 2. 进行试点筛选以验证测定。目标 3. 测试已确认的针对野生型 HIV 病毒和对已知衣壳抑制剂具有抗性的突变病毒的抗病毒活性。