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（由申请方提供）：本研究的长期目标是鉴定作为抑制HIV-1整合酶（IN）和预防HIV-1复制的潜在临床候选药物的新型分子。细胞染色质连接LEDGF融合蛋白通过与IN的结合在HIV复制中起重要作用，使其成为抗病毒治疗的理想靶点。拟议的研究旨在设计基于药效团的模型，以挖掘分子数据库中的新型化合物，这些化合物将破坏IN-LEDGF复合物的形成。具体目标I是针对使用晶体学数据作为平台来设计具有独立于催化位点的新机制的位点特异性IN抑制剂。从IN-LEDGF复合物模型中鉴定出的最初几组化合物将提供未来基于活性的模型，以增强对其他先导分子的发现。特定目标II旨在筛选ADMET模拟中预测具有有利理化性质的IN和LEDGF拮抗剂亚群，以生成新的Q-SAR模型，旨在鉴定显示体内活性的新抑制剂。具体目标III旨在确定已鉴定的IN抑制剂与已知抗HIV化合物在体外和基于细胞的测定中组合的协同作用。艾滋病是世界上最严重的健康问题之一。2005年，世界卫生组织和美国政府共同努力，增加发展中国家抗逆转录病毒药物的供应，因为疾病预防控制中心宣布，美国艾滋病感染人数已达到100万。2004年至2006年，北美艾滋病患者人数增加了16.7%，而联合国艾滋病规划署（UNAIDS）的报告显示，撒哈拉以南非洲增加了4.7%，东南亚增加了5.6%，东亚增加了21%。如果没有有效的抗病毒治疗方案，HIV受试者最终将死于HIV-1免疫缺陷。公共卫生相关性：耐药病毒株的出现和全球HIV-1感染的指数增加反映了开发具有新作用机制的新HIV-1治疗剂以纳入HAART药物方案的紧迫性。