DEVELOPING A POTENT INHIBITOR OF HIV-I INTEGRASE

开发有效的 HIV-1 整合酶抑制剂

• 批准号: 6181569
• 负责人: NAIJIE JING
• 金额: $ 21.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6181569
• 关键词: antiAIDS agent; antiviral agents; chemical models; chemical structure function; circular dichroism; computer simulation; drug design /synthesis /production; enzyme inhibitors; human immunodeficiency virus 1; integrase; nuclear magnetic resonance spectroscopy; nucleic acid chemical synthesis; oligonucleotides; structural biology; tissue /cell culture

DESCRIPTION: (Adapted from Applicant's Abstract) The goal of this work is to develop novel inhibitors of HIV-1 integrase (IN) as potent anti-HIV therapeutic drugs. Although combination therapy, which uses two or more drugs simultaneously to inhibit HIV activity, can reduce the HIV virus to undetectable levels in the blood of many HIV-positive patients, the viruses in T cells are still capable of replicating and infecting other cells. The development of new agents against HIV-1 IN, which may eliminate HIV-1 from intracellular sites would be a major advance in the treatment of HIV infection. The newly designed oligonucleotide, T30695, has shown effective interaction with HIV-1 IN in vitro (IC50 = 50 nM), and it may have the potential of stopping replication of HIV-1 virus by blocking integration in vivo. In order to improve the efficiency of its inhibition of HIV-1 IN activity for preclinical and phase I tests, T30695 will be used as a lead compound to design and select novel candidates for anti-HIV therapies with stronger inhibition of HIV-1 IN. SA 1. The structure-based design of inhibitors of HIV-1 IN will be performed using 3D molecular modeling based upon the molecular model of the T30695-IN complex, which was constructed from X-ray crystal and NMR structures of HIV-1 IN and T30695. These candidates, stored in a database, will be synthesized for further tests. SA 2. Measurement of HIV IN inhibition (IC50) of the rationally designed candidates will be carried out with a 96-well HIV-1 scintillation proximity assay (SPA). The inhibition of HIV-1 replication (EC50) will be measured in a virus culture assay, using the candidates with the lowest IC50 values, as assessed by SPA. SA 3. The biophysical characteristics, including 3D structure, of the rationally designed candidates for HIV-1 IN inhibition will be determined by NMR, modeling, CD, UV, and kinetics. Then, by combining the biophysical information with the anti-HIV activity, IC50 and EC50, a 3D QSAR (quantitative structure-activity relationships) will be conducted to select the best bioactive candidate as a potent inhibitor of HIV-1 IN for preclinical and phase I tests.

描述：（改编自申请人的摘要）这项工作的目标是 开发新型 HIV-1 整合酶 (IN) 抑制剂作为有效的抗 HIV 治疗药物 药物。尽管联合疗法使用两种或多种药物 同时抑制HIV活性，可以减少HIV病毒 许多艾滋病毒阳性患者血液中的病毒水平无法检测到 T 细胞仍然能够复制和感染其他细胞。这 开发抗 HIV-1 IN 的新药物，可能消除 HIV-1 细胞内位点将是治疗艾滋病毒感染的重大进展。 新设计的寡核苷酸T30695已显示出有效的相互作用 HIV-1 在体外（IC50 = 50 nM），并且它可能具有潜力 通过阻断体内整合来阻止 HIV-1 病毒的复制。为了 提高其抑制 HIV-1 IN 活性的效率 临床前和 I 期测试，T30695 将作为先导化合物进行设计 并选择具有更强抑制作用的抗 HIV 疗法的新候选药物 HIV-1 输入。 SA 1. HIV-1 IN抑制剂的基于结构的设计将是 使用基于分子模型的 3D 分子建模进行 T30695-IN 复合物，由 X 射线晶体和 NMR 结构构建而成 HIV-1 IN 和 T30695。这些候选人将被存储在数据库中 合成用于进一步测试。 SA 2. HIV IN 抑制 (IC50) 的测量 合理设计的候选者将使用96孔HIV-1进行 闪烁邻近分析（SPA）。 HIV-1复制的抑制（EC50） 将通过病毒培养测定进行测量，使用具有最低的候选者 IC50 值，由 SPA 评估。 SA 3.生物物理特性， 包括 3D 结构，合理设计的 HIV-1 IN 候选物 抑制作用将通过 NMR、建模、CD、UV 和动力学来确定。然后，通过 将生物物理信息与抗 HIV 活性、IC50 和 EC50，3D QSAR（定量结构-活性关系）将 旨在选择最佳生物活性候选物作为有效的 HIV-1 抑制剂 IN 用于临床前和 I 期测试。