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

描述（由申请人提供）：靶向HIV病毒转录酶或蛋白酶的药物用于高效抗逆转录病毒治疗（HAART）鸡尾酒，延长了艾滋病患者的生命。不幸的是，这些药物与严重的毒性相关，不能控制某些患者中的病毒复制，并且由于病毒耐药性而无效。HIV复制对整合酶的绝对需求，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靶点。最近引入的整合酶靶向药物雷特格韦已经验证了这种酶作为一个非常有前途的HIV/AIDS治疗靶点。我们对具有β-二酮酸基序的新型生物电子等排取代的HIV整合酶的小分子抑制剂的研究已经鉴定出具有个位数微摩尔效力的新型HIV整合酶抑制剂。我们建议进行铅优化，以提高效力，并评估其治疗艾滋病毒感染的潜力。我们将联合收割机结合药物化学与计算机辅助药物设计和生物测试的效力，选择性和毒性。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（包括来自AIDS患者的耐药分离株）的细胞培养测试的创新整合。HIV-1感染的人外周血单核细胞（PBMC）培养物将用于检测化合物阻断HIV复制的能力。将使用未感染的PBMC以及CEM白血病和Vero细胞测试化合物的毒性以评估治疗指数。该项目的成功将提供新型“药物样”整合酶抑制剂作为临床前HIV/AIDS药物开发候选物;并增加我们在设计新型HIV整合酶靶向抗病毒剂方面的知识。公共卫生相关性：该拨款提案旨在开发抑制HIV整合酶的新化合物以治疗艾滋病。PI发现了有效的整合酶抑制剂。资助提案的目标是优化活性和测试毒性。

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.