Discovery and Optimization of Novel Integrase Inhibitors as Anti-HIV Agents

作为抗 HIV 药物的新型整合酶抑制剂的发现和优化

• 批准号: 7756787
• 负责人: John K Buolamwini
• 金额: $ 24.46万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 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/7756787
• 关键词: AIDS/HIV problem; Acids; Acquired Immunodeficiency Syndrome; Amides; Anti-HIV Agents; Antiviral Agents; Applications Grants; Behavior; Benzoic Acids; Biological Assay; Biological Testing; Cell Culture Techniques; Cells; Chalcone; Chalcones; Clinical; Clinical Drug Development; Combinatorial Synthesis; Computer Assisted; Computing Methodologies; Digit structure; Docking; Drug Delivery Systems; Drug Design; Drug resistance; Enzymes; Exploratory/Developmental Grant; Face; Flavones; Funding; Goals; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Highly Active Antiretroviral Therapy; Human; Inhibitory Concentration 50; Integrase; Integrase Inhibitors; Knowledge; Lead; Life; Life Cycle Stages; Ligands; Maps; Marketing; Modeling; Modification; Molecular; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmaceutical Preparations; Quantitative Structure-Activity Relationship; Recombinants; Relative (related person); Resistance; Salicylic Acids; Series; Solutions; Source; Staging; Structure; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicity Tests; Transcriptase; Variant; Vero Cells; Viral; Viral Drug Resistance; Virus; analog; base; compliance behavior; cytotoxicity test; design; drug development; flavone; improved; inhibitor/antagonist; innovation; insight; leukemia; molecular dynamics; mutant; novel; pharmacophore; pre-clinical; prevent; public health relevance; resistance mutation; small molecule; success; therapeutic development; therapeutic target

DESCRIPTION (provided by applicant): Drugs targeting the HIV virus transcriptase or protease are used in highly active antiretroviral therapy (HAART) cocktails that have prolonged the lives of AIDS patients. Unfortunately, these drugs are associated with severe toxicities, unable to control viral replication in some patients, and are rendered in effective by viral drug resistance. The absolute requirement of the integrase enzyme for HIV replication, and the fact that it has no host cell counterpart, make it an attractive drug development target. The recent introduction of the integrase targeted drug raltegravir has validated this enzyme as a very promising HIV/AIDS therapeutic target. Our studies on small molecule inhibitors of HIV integrase with novel bioisosteric replacement of the beta-diketo acid motive have led to the identification of novel HIV integrase inhibitors with single digit micromolar potency. We propose to undertake lead optimization to increase the potency and assess their potential to treat HIV infection. We will combine medicinal chemistry with computer-aided drug design and biological testing for potency, selectivity and toxicity. An innovative integration of docking, molecular dynamics simulations, structure-based design, chemoinformatics, pharmacophore mapping and three dimensional quantitative structure-activity relationships (3D-QSAR), parallel combinatorial synthesis, bioassays using recombinant wild type and mutant HIV integrase variants, cell culture testing against viral replication including drug resistant isolates from AIDS patients, will be applied. HIV-1 infected human peripheral blood mononuclear cell (PBMC) cultures will be used to test the ability of compounds to block HIV replication. Toxicity of compounds will be tested using uninfected PBMCs as well as CEM leukemia and Vero cells to assess therapeutic index. The success of this project will provide novel "drug- like" integrase inhibitors as preclinical HIV/AIDS drug development candidates; and increase our knowledge in the design of novel HIV integrase targeted antiviral agents. PUBLIC HEALTH RELEVANCE: This grant proposal seeks to develop new compounds for inhibiting HIV integrase to treat AIDS. The PI has discovered potent integrase inhibitors. The objectives of the grant proposal are to optimize activity and test toxicity.

描述（由申请人提供）：针对 HIV 病毒转录酶或蛋白酶的药物用于高效抗逆转录病毒疗法 (HAART) 鸡尾酒，可延长艾滋病患者的生命。不幸的是，这些药物具有严重的毒性，无法控制某些患者的病毒复制，并且由于病毒耐药性而变得无效。 HIV复制对整合酶的绝对要求，以及它没有宿主细胞对应物的事实，使其成为有吸引力的药物开发目标。最近推出的整合酶靶向药物拉替拉韦已证实该酶是一个非常有前途的艾滋病毒/艾滋病治疗靶点。我们对具有β-二酮酸基序的新型生物电子等排替代的HIV整合酶小分子抑制剂的研究导致了具有个位数微摩尔效力的新型HIV整合酶抑制剂的鉴定。我们建议进行先导化合物优化，以提高其效力并评估其治疗 HIV 感染的潜力。我们将药物化学与计算机辅助药物设计和效力、选择性和毒性的生物测试相结合。将应用对接、分子动力学模拟、基于结构的设计、化学信息学、药效团作图和三维定量结构-活性关系（3D-QSAR）、平行组合合成、使用重组野生型和突变型HIV整合酶变体的生物测定、针对病毒复制的细胞培养测试（包括来自艾滋病患者的耐药分离株）的创新整合。 HIV-1 感染的人外周血单核细胞 (PBMC) 培养物将用于测试化合物阻止 HIV 复制的能力。将使用未感染的PBMC以及CEM白血病和Vero细胞来测试化合物的毒性，以评估治疗指数。该项目的成功将为临床前艾滋病毒/艾滋病药物开发候选药物提供新型“类药”整合酶抑制剂；并增加我们在设计新型 HIV 整合酶靶向抗病毒药物方面的知识。公共健康相关性：该拨款提案旨在开发新的化合物来抑制 HIV 整合酶以治疗艾滋病。 PI 发现了有效的整合酶抑制剂。拨款提案的目标是优化活性并测试毒性。