Illuminating Old Catalysts for the Synthesis of Anti-infective HIV Peptides

阐明用于合成抗感染艾滋病毒肽的旧催化剂

基本信息

批准号：
10270506
负责人：
Steven Bloom
金额：
$ 21.21万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270506
关键词：
Acquired Immunodeficiency Syndrome Active Sites Address Affinity Amino Acids Animals Anti-HIV Agents Anti-Infective Agents Anti-Retroviral Agents Antigens Binding Biochemical Biological Availability Biological Products Biology CD4 Positive T Lymphocytes Capsid Cations Cells Chemicals Collaborations Communicable Diseases Complex Computer Models Computer software Computing Methodologies Development Diagnosis Disease Dose Drug resistance Early treatment Environmental Risk Factor Enzyme Inhibitor Drugs Evaluation Goals Guanine HIV HIV Infections HIV-1 HIV-1 protease In Vitro Individual Infection Interruption Jurkat Cells Laboratories Lead Length Leukocytes Life Life Cycle Stages Metabolic Methods Mind Modeling Mutation Nucleocapsid Nucleocapsid Proteins Outcomes Research Peptides Persons Pharmaceutical Preparations Pharmacotherapy Population Process Production Property Protease Inhibitor Protein Precursors Proteins Proteolysis Public Health RNA RNA Binding Reporting Role SERPINA4 gene Sampling Savings Series Side Structure Structure-Activity Relationship Synthesis Chemistry Testing Therapeutic Toxic effect Treatment Failure Vaccines Variant Viral Viral Genome Viral Load result Virion Virus Virus Replication Zinc Fingers analog antiretroviral therapy assay development base catalyst cellular targeting combat compliance behavior drug candidate drug development improved in silico inhibitor/antagonist innovation insight next generation novel therapeutics pandemic disease particle protein complex recruit research clinical testing resistant strain stem virtual virtual model

项目摘要

PROJECT SUMMARY Since its first recognition in the early 1980s, HIV has claimed more than 32 million lives worldwide. Before the introduction of antiretroviral therapy in the 1990s, an individual infected with HIV could progress to AIDS the most advanced stage of HIV infection, and the deadliest (~11-month survival after diagnosis)very quickly. But today, with early treatment, a person diagnosed with HIV can live nearly as long as someone without the disease. Unfortunately, there is no cure for HIV. More troubling, the current repertoire of life-saving antiretroviral drugs that keep the HIV infection in check are losing their hold over the infection. In the last decade, poor patient compliance (skipping daily antiretroviral doses) combined with environmental factors have led to mutations in the HIV virus that lead to drug-resistant strains. Now more than ever, new therapies that attack new viral targets are desperately needed to combat the global HIV pandemic. Like all viruses, the life-cycle of HIV-1 relies on host cell machinery. The virus infects CD4+ T-lymphocytes (a specific population of white blood cells) and uses the cell to replicate the viral genome, assemble new virus particles, and unleash copies of the virus to infect more CD4+ T-lymphocytes. The formation of new virus particles can only occur if the viral RNA is identified among the vast array of other RNAs within the cell and successfully recruited to the Gag complex. This essential recognition and recruitment process is accomplished entirely by the Gag-nucleocapsid protein (NCp7). In brief, the nucleocapsid identifies a conserved region of viral RNA (known as RNA), located on stem loop 3 (SL3) of the viral RNA strand and then helps to package the collected RNA strands into a new virus particle. If this assembly process is interrupted, the virus will be unable to produce replication competent virions and to exit the host cell, thereby inhibiting the final stages of viral replication. Those considerations in mind, the SL3RNA-NCp7 complex has become a prime target for next- generation antiretrovirals. The quest for molecules which selectively inhibit the SL3RNA-NCp7 interaction has followed several lines of approach. One promising avenue has been to use peptides. To this end, a synthetic hexapeptide (HKWPWW; HP1) was recently described that showed high affinity for the SL3 tetraloop of RNA, disrupting the binding of NCp7 and causing inhibition of HIV-1 replication in vitro. While a promising lead for drug development, the mechanism by which HP1 recognizes and binds to SL3-RNA is still ill-defined. Our goals will be to interrogate the structure activity relationships for HP1 binding to RNA using high-throughput amino acid diversification (substituting key residues in HP1 for non-proteinogenic variants) in tandem with in silico modeling. From these insights, structural optimization of HP1 to enhance its binding affinity to RNA will be explored as a contemporary strategy to develop a new class of inhibitors of HIV-1 replication.

项目概要自 20 世纪 80 年代初首次被认识以来，艾滋病毒已夺去了全世界超过 3200 万人的生命。随着 20 世纪 90 年代抗逆转录病毒疗法的引入，感染艾滋病毒的个体可能会发展为艾滋病 – HIV 感染的最晚期阶段，也是最致命的阶段（诊断后存活约 11 个月）——速度非常快。但如今，通过早期治疗，被诊断出艾滋病毒感染者的寿命几乎可以与未感染艾滋病毒的人一样长。不幸的是，目前还没有治愈艾滋病毒的方法。在过去的十年里，那些将艾滋病毒感染控制在药物中的药物正在失去对感染的控制。依从性（跳过每日抗逆转录病毒剂量）与环境因素相结合导致了突变现在，新疗法比以往任何时候都更能攻击新的病毒靶点。抗击全球艾滋病毒大流行迫切需要这些药物。与所有病毒一样，HIV-1 的生命周期依赖于宿主细胞机制。该病毒感染 CD4+ T 淋巴细胞。（特定的白细胞群体）并使用该细胞复制病毒基因组，组装新病毒颗粒，并释放病毒副本来感染更多 CD4+ T 淋巴细胞，形成新病毒。只有在细胞内大量其他 RNA 中识别出病毒 RNA 时，才会出现颗粒，并且成功招募到 Gag 综合体这一重要的认可和招募过程已经完成。完全由 Gag 核衣壳蛋白 (NCp7) 完成。简而言之，核衣壳识别病毒的保守区域。 RNA（称为RNA），位于病毒RNA链的茎环3（SL3）上，然后帮助包装将RNA链收集成新的病毒颗粒，如果这个组装过程被中断，病毒将无法组装。产生具有复制能力的病毒颗粒并离开宿主细胞，从而抑制病毒的最后阶段考虑到这些因素，SL3RNA-NCp7 复合物已成为下一步的主要目标。一代抗逆转录病毒药物。对选择性抑制 SL3RNA-NCp7 相互作用的分子的探索遵循了几条路线为此，一种有希望的途径是使用合成的六肽（HKWPWW； HP1) 最近被描述为对 RNA 的 SL3 四环表现出高亲和力，破坏了 NCp7 并在体外抑制 HIV-1 复制，虽然是药物开发的一个有希望的先导，但 HP1 识别并结合 SL3-RNA 的机制仍然不明确，我们的目标是探究。使用高通量氨基酸多样化分析 HP1 与 RNA 结合的结构活性关系（用 HP1 中的关键残基替换非蛋白原变体）与计算机模拟相结合。见解，HP1 的结构优化以增强其与 RNA 的结合亲和力将作为当代研究进行探索开发一类新型 HIV-1 复制抑制剂的策略。