Design and discovery of HIV-1 IN inhibitors with a novel mechanism of action

具有新颖作用机制的 HIV-1 IN 抑制剂的设计和发现

• 批准号: 7674220
• 负责人: Tino Wilson Sanchez
• 金额: $ 4.12万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674220
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Active Sites; Address; Affinity; Africa South of the Sahara; Amino Acids; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Antiviral Therapy; Binding; Binding Sites; Biological; Biological Assay; Biological Testing; Catalytic Domain; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Chimeric Proteins; Chromatin; Clinical; Collaborations; Complex; Computer software; Crystallography; Data; Data Set; Databases; Descriptor; Developed Countries; Developing Countries; Docking; Drug Design; Drug Kinetics; Drug resistance; Epithelial; Excretory function; Exhibits; FDA approved; Far East; Future; Goals; Government; Growth Factor; HIV; HIV-1; HIV-1 integrase; Health; Highly Active Antiretroviral Therapy; Housing; Human Genome; Immunologic Deficiency Syndromes; In Vitro; Individual; Infection; Integrase; Integrase Inhibitors; Investigation; Joints; Laboratories; Lead; Libraries; Life Cycle Stages; Ligands; Mass Spectrum Analysis; Measures; Metabolism; Methods; Mining; Modeling; Molecular; North America; Oral; Patients; Permeability; Pharmaceutical Preparations; Phase III Clinical Trials; Play; Predisposition; Prevention; Property; Proteins; Reporting; Research; Reverse Transcription; Role; Running; Screening procedure; Shapes; Side; Site; Site-Directed Mutagenesis; Solubility; Structure; Testing; Therapeutic; Toxic effect; Training; Transcription Coactivator; Treatment Protocols; United Nations; Validation; Viral; Work; World Health Organization; absorption; base; chemical property; design; dimer; dosage; drug resistant virus; enol; in vivo; inhibitor/antagonist; lens; magnesium ion; model design; monomer; mutant; novel; pharmacophore; predictive modeling; prevent; professor; programs; protein complex; public health relevance; simulation; tool; transcriptional coactivator p75; viral DNA

DESCRIPTION (provided by applicant): The long term objective of this study is to identify novel molecules as potential clinical candidates for the inhibition of HIV-1 integrase (IN) and the prevention of HIV-1 replication. Cellular chromatin-tethering LEDGF fusion protein was reported to be essential in HIV replication through an association with IN, making it an ideal target for antiviral therapy. The proposed studies aim to design pharmacophore-based models to mine molecular databases for novel compounds that will disrupt IN-LEDGF complex formation. Specific aim I is directed at using crystallography data as a platform to design site-specific IN inhibitors with a novel mechanism independent of catalytic site. Initial sets of compounds identified from IN-LEDGF complex models will provide future activity-based models to enhance discovery for additional lead molecules. Specific aim II is designed to filter subpopulations of IN and LEDGF antagonists with favorable physiochemical properties predicted in ADMET simulations to generate new Q-SAR models that will aim to identify new inhibitors showing activity in vivo. Specific aim III is designed to determine the synergistic effects of identified IN inhibitors in combination with known anti-HIV compounds in vitro and in cell-based assays. AIDS is one of the world's most serious health problems. In 2005, the world health organization and the U.S. government created a joint effort to increase the availability of antiretroviral drugs to developing countries as the CDC announced HIV had reached one million infections in the U.S. Between 2004 and 2006, there was a 16.7 % increase in the number of AIDS patients in North America, compared with a 4.7 % increase in Sub-Saharan Africa, a 5.6 % in South East Asia, and 21 % increase in East Asia as reported by a joint United Nations Program on HIV/AIDS (UNAIDS). Without an effective antiviral regimen HIV subjects will eventually succumb to HIV-1 immunodeficiency. PUBLIC HEALTH RELEVANCE: The emergence of drug resistant viral strains and the exponential increase in HIV-1 infections worldwide echoes an urgency to develop new HIV-1 therapeutics with novel mechanisms of action to incorporate into HAART drug regimes.

描述（由申请人提供）：这项研究的长期目标是将新的分子识别为抑制HIV-1整合酶（IN）和预防HIV-1复制的潜在临床候选者。据报道，细胞染色质螺旋蛋白LEDGF融合蛋白通过与IN的关联在HIV复制中至关重要，这使其成为抗病毒治疗的理想靶标。拟议的研究旨在设计基于药丸的模型，以开采分子数据库的新化合物，这些新化合物会破坏脑海中的复合物的形成。具体目的I致力于使用晶体学数据作为平台，在具有独立于催化位点的新型机制的抑制剂中设计位点特异性。从LEDGF复合模型中鉴定出的化合物的初始集将提供基于活动的模型，以增强其他铅分子的发现。特定的目标II旨在过滤IN和LEDGF拮抗剂的亚群，其在ADMET模拟中预测的具有良好的生理化学特性，以生成新的Q-SAR模型，该模型将旨在鉴定出新的抑制剂，显示新的抑制剂。特定的目标III旨在确定抑制剂中鉴定出的协同作用，并在体外和基于细胞的测定中结合使用已知的抗HIV化合物。艾滋病是世界上最严重的健康问题之一。 2005年，由于疾病预防控制中心宣布艾滋病毒的艾滋病毒在2004年至2006年之间，美国卫生局宣布艾滋病毒在美国达到100万次感染，因此在2005年，世界卫生组织和美国政府为增加抗逆转录病毒药物的供应量增加了16.7％，北美的艾滋病患者的数量增加了16.7％，而北美地区的艾滋病数量增加了4.7％，而南部的东东地区则增长了4.7％，而远东地区则增加了5.6％，而远东地区的艾滋病患者则增加了16.7％。艾滋病毒/艾滋病（UNAIDS）的国家计划。没有有效的抗病毒治疗艾滋病毒受试者，最终将屈服于HIV-1免疫缺陷。公共卫生相关性：抗药性病毒菌株的出现以及全世界HIV-1感染的指数增加与开发新的HIV-1治疗剂的紧迫性具有新型的作用机制，可以纳入HAART药物制度。