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：（根据申请人的摘要改编）这项工作的目的是 开发新型HIV-1整合酶（IN）作为有效的抗HIV治疗的抑制剂 毒品。虽然使用两种或多种药物的联合疗法 同时抑制HIV活性，可以将HIV病毒降低到 许多HIV阳性患者的血液中无法检测到的水平，病毒 T细胞仍然能够复制和感染其他细胞。这 开发针对HIV-1 IN的新代理，这可能会消除HIV-1 细胞内部位将是治疗HIV感染的重大进展。 新设计的寡核苷酸T30695显示了有效的相互作用 在体外（IC50 = 50 nm）中使用HIV-1，它可能具有 通过在体内阻止整合来阻止HIV-1病毒的复制。为了 提高其抑制HIV-1在活性中的效率 临床前和I期测试，T30695将用作设计的铅化合物 并选择具有更强抑制的抗HIV疗法的新型候选者 HIV-1 in。 SA 1。基于结构的HIV-1抑制剂在 使用3D分子建模基于分子模型进行 T30695-IN复合物，由X射线晶体和NMR结构构建 HIV-1和T30695。这些存储在数据库中的候选人将是 合成以进行进一步测试。 SA 2。抑制艾滋病毒的测量（IC50） 理性设计的候选人将使用96孔HIV-1进行 闪烁接近测定法（SPA）。 HIV-1复制的抑制（EC50） 使用最低的候选者，将在病毒培养测定中测量 IC50值，如水疗中心评估。 SA 3。生物物理特征， 包括3D结构，用于HIV-1的合理设计的候选者 抑制作用将由NMR，建模，CD，UV和动力学确定。然后，by 将生物物理信息与抗HIV活性相结合，IC50和 EC50，3D QSAR（定量结构活性关系）将是 进行选择最佳生物活性候选者作为HIV-1的有效抑制剂 用于临床前和I期测试。