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Intermolecular cooperativity in the action of antiviral agents

抗病毒药物作用中的分子间协同作用

基本信息

批准号：
8415537
负责人：
ROBERT F SILICIANO
金额：
$ 26.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-23 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415537
关键词：
Affect Anti-Retroviral Agents Antiviral Agents Binding Binding Sites Biochemical Biological Assay Characteristics Clinical Clinical Trials Detection Dimensions Dose Drug Design Drug Targeting Drug resistance Enzymes Exhibits Goals HIV HIV-1 Highly Active Antiretroviral Therapy Immune system Infection Inhibitory Concentration 50 Laboratories Life Cycle Stages Ligands Measures Methods Molecular Mutation Nucleosides Outcome Peptide Hydrolases Pharmaceutical Preparations Predisposition Protease Inhibitor Proteins Reaction Regimen Relative (related person)Reverse Transcriptase Inhibitors Shapes System Testing Vaccines Variant Viral Viremia Virus clinically relevant drug development env Gene Products improved in vitro Assay in vivo indexing maspin mutant neutralizing antibody neutralizing monoclonal antibodies non-nucleoside reverse transcriptase inhibitors novel nucleotide analog reconstitution research study resistance mutation response vaccine development

项目摘要

Treatment with appropriate combinations of antiretroviral drugs can reduce HIV-1 viremia to below the limit of detection and allow reconstitution of the immune system. The correct choice of antiretroviral drugs is critical for achieving and maintaining suppression of viral replication. Interestingly, there is no widely accepted system for comparing the antiviral activity of different drugs. Previous studies from this lab have shown that the inhibitory potential of antiretroviral drugs is strongly dependent upon a previously ignored factor termed here the slope parameter. This parameter describes the steepness of the dose-response curve. The inhibitory potential of antiretroviral drugs, described in a new index developed by this lab, varies for different classes of antiretroviral drugs by over 10 logs (10,000,000,000 fold!) in a manner that is strongly influence by the slope parameter. Thus the slope parameter is a critical missing dimension in the analysis of the suppressive potential of antiretroviral drugs. This proposal seeks to understand the molecular mechanisms underlying this effect and to use that information to guide the development of drugs and vaccines that will maximally suppress viral replication. The first specific aim is to test a mechanistic hypothesis involving a unique form of intermolecular cooperativity which can explain the shapes of dose-response curves for antiviral drugs. This hypothesis will be tested in a very specific way using phenotypic mixing experiments with viruses carrying both wild type and mutant forms of the proteins targeted by the drugs. The second aim is to understand the high magnitude and drug-to-drug variability of the slope parameter for the protease inhibitor class of antiretroviral drugs. Among the drug classes tested to date, the protease inhibitors show the highest slope values. As a result, clinical concentrations of some of these drugs can inhibit single round infections by ~10 logs. This project seeks to identify the mechanism underlying this extraordinary susceptibility of HIV-1 to inhibition by some protease inhibitors. The third specific aim is to apply this method of analysis to novel classes of antiretroviral drugs. Since a high slope value is critical for achieving multi-log inhibition of single round infection, the proposed analyses could identify drug classes that are likely to be particularly effective in vivo. The fourth aim is to determine the effect of drug resistance mutations on dose-response curve slope. Correct prediction of the clinical consequences of drug resistance mutations requires an understanding of the effects of the mutations on the slope parameter. The final aim is to measure the slope parameter of neutralizing antibodies directed at the HIV-1 envelope protein since concept of dose-response curve slope also applies to vaccine-induced effector mechanisms including neutralizing antibodies.

适当联合抗逆转录病毒药物治疗可将 HIV-1 病毒血症降低至低于检测限并允许重建免疫系统。正确的选择是抗逆转录病毒药物对于实现和维持病毒复制抑制至关重要。有趣的是，没有广泛接受的系统来比较不同药物的抗病毒活性。该实验室之前的研究表明，抗逆转录病毒药物的抑制潜力很强取决于先前被忽略的因素，此处称为斜率参数。这个参数描述剂量反应曲线的陡度。抗逆转录病毒药物的抑制潜力，该实验室开发的新索引中描述了不同类别的抗逆转录病毒药物的差异超过 10 个对数（10,000,000,000 倍！），其方式受到斜率参数的强烈影响。因此斜率参数是抑制潜力分析中的一个关键缺失维度抗逆转录病毒药物。该提案旨在了解其背后的分子机制效果并利用该信息来指导药物和疫苗的开发，从而最大限度地抑制病毒复制。第一个具体目标是测试涉及独特的机制假设分子间协同作用的形式，可以解释抗病毒药物的剂量反应曲线的形状药物。该假设将通过表型混合实验以非常具体的方式进行检验携带药物靶向蛋白质的野生型和突变型病毒。第二个目标是为了了解蛋白酶的斜率参数的高幅度和药物与药物之间的变异性抑制剂类抗逆转录病毒药物。在迄今为止测试的药物类别中，蛋白酶抑制剂显示最高斜率值。因此，其中一些药物的临床浓度可以抑制单轮感染约 10 个日志。该项目旨在确定这一现象背后的机制 HIV-1 对某些蛋白酶抑制剂的抑制非常敏感。第三个具体目标是将这种分析方法应用于新型抗逆转录病毒药物。由于高斜率值是对于实现单轮感染的多对数抑制至关重要，所提出的分析可以确定可能在体内特别有效的药物类别。第四个目标是确定效果剂量反应曲线斜率上的耐药突变。正确预测临床耐药突变的后果需要了解突变的影响关于斜率参数。最终目的是测量中和抗体的斜率参数针对 HIV-1 包膜蛋白，因为剂量反应曲线斜率的概念也适用于疫苗诱导的效应机制，包括中和抗体。