Structure Aided Design of RNA-Directed Inhibitors of HIV-1

RNA 导向的 HIV-1 抑制剂的结构辅助设计

基本信息

批准号：
8496741
负责人：
Justin Thomas Low
金额：
$ 2.76万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2009-06-22 至 2014-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496741
关键词：
AIDS/HIV problem Accounting Acute Acylation Affect Affinity Algorithms Anti-Retroviral Agents Antisense Oligonucleotides Back Base Pairing Binding Biological Assay Capillary Electrophoresis Cell membrane Cells Clinical Collaborations Complementary DNA Complex DNA Sequence Rearrangement Development Disease Drug Targeting Drug abuse Effectiveness Environment Enzymes Genome Genomics Goals HIV HIV Genome HIV Infections HIV-1 Health Health Services Accessibility Highly Active Antiretroviral Therapy Human Hydroxyl Radical Individual Infection Integrase Laboratories Learning Life Methodology Molecular Conformation National Cancer Institute Nucleotides Oligonucleotides Patients Peptide Hydrolases Pharmaceutical Preparations Population Primer Extension Prisons Property RNA RNA-Directed DNA Polymerase Regimen Research Research Training Resistance development Resolution Reverse Transcriptase Inhibitors Reverse Transcription Sampling Site Structure Techniques Technology Tertiary Protein Structure Testing Therapeutic Thermodynamics Viral Viral Envelope Proteins Viral Proteins Virion Virus Work analog base design drug candidate drug development drug of abuse effectiveness measure experience inhibitor/antagonist locked nucleic acid novel research study

项目摘要

DESCRIPTION (provided by applicant): Infection with HIV disproportionately affects drug dependent individuals. Furthermore, due to a variety of factors including comorbid conditions, decreased compliance, and increased development of resistance, the effectiveness of currently available HIV treatments is reduced in this population. The need for new ways of targeting HIV is therefore particularly acute in this population. However, despite the wealth of ongoing research in HIV drug development, most new drug candidates continue to target only a few well-defined protein domains, chosen for their functional importance in HIV replication. Targeting the RNA genome itself in a structure-directed manner presents an opportunity to greatly expand the repertoire of potential target sites for anti-HIV therapeutics. The long term goals of this project are to investigate new mechanisms of inhibiting HIV by targeting its RNA genome. To accomplish this, I will combine the unique structure-probing technologies developed in the sponsor laboratory with advances in the fields of antisense oligonucleotide inhibitor design and computational RNA structure determination to study novel ways of inhibiting HIV by directly targeting the genome using two different mechanisms. In addition to studying basic mechanisms of retroviral inhibition at the laboratory bench, I will also learn about the disease from a bedside perspective by spending 10% of my effort engaged in a unique clinical training and research experience with HIV patients in drug-abusing and prison populations. My specific aims are to (1) inhibit HIV by inducing large-scale structural rearrangements in important regulatory domains in the HIV genome and (2) inhibit HIV reverse transcription by sterically blocking the enzyme using high-affinity antisense oligonucleotide analogs.

描述（由申请人提供）：艾滋病毒感染对药物依赖者的影响尤为严重。此外，由于多种因素，包括合并症、依从性下降和耐药性增加，目前可用的艾滋病毒治疗对该人群的有效性降低。因此，这一人群迫切需要寻找针对艾滋病毒的新方法。然而，尽管艾滋病毒药物开发方面正在进行大量研究，但大多数新候选药物仍然只针对少数明确的蛋白质结构域，这些蛋白质结构域的选择是因为它们在艾滋病毒复制中的功能重要性。以结构导向的方式靶向 RNA 基因组本身提供了一个机会，可以大大扩展抗 HIV 治疗的潜在靶位点。该项目的长期目标是研究通过靶向 RNA 基因组来抑制 HIV 的新机制。为了实现这一目标，我将把申办者实验室开发的独特结构探测技术与反义寡核苷酸抑制剂设计和计算RNA结构测定领域的进展相结合，通过使用两种不同的机制直接靶向基因组来研究抑制HIV的新方法。除了在实验台上研究逆转录病毒抑制的基本机制外，我还会从床边的角度了解这种疾病，花10%的精力在吸毒和监狱的艾滋病患者身上进行独特的临床培训和研究经验人口。我的具体目标是（1）通过在 HIV 基因组的重要调控域中诱导大规模结构重排来抑制 HIV，以及（2）通过使用高亲和力反义寡核苷酸类似物对酶进行空间阻断来抑制 HIV 逆转录。