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

• 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
• 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

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.

项目总结 自20世纪80年代初首次被发现以来，艾滋病毒已在全球夺走了3200多万人的生命。在此之前 20世纪90年代引入抗逆转录病毒疗法后，感染艾滋病毒的个人可能进展为艾滋病 艾滋病毒感染的最晚期，以及最致命的(确诊后存活约11个月)非常快。 但今天，通过早期治疗，被诊断出感染艾滋病毒的人几乎可以和没有感染艾滋病毒的人一样长寿。 疾病。不幸的是，艾滋病毒是无法治愈的。更令人不安的是，目前救命的抗逆转录病毒药物 控制艾滋病毒感染的药物正在失去对感染的控制。在过去的十年里，可怜的病人 依从性(跳过每天的抗逆转录病毒剂量)与环境因素相结合，导致了 导致抗药性菌株的HIV病毒。现在比以往任何时候都更多的是攻击新的病毒目标的新疗法 是抗击全球艾滋病毒大流行的迫切需要。 像所有病毒一样，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 (一组特定的白细胞)，并使用该细胞复制病毒基因组，组装新病毒 颗粒，并释放病毒的副本，感染更多的CD4+T淋巴细胞。新病毒的形成 只有在细胞内大量的其他RNA中发现了病毒RNA，并且 成功地被招募到恶作剧情结。这一重要的认可和招聘过程已经完成。 完全由Gag-核衣壳蛋白(NCp7)决定。简而言之，核衣壳识别病毒的保守区域。 核糖核酸(称为SL3RNA)，位于病毒链的茎环3(SL3)上，然后帮助包装 收集的核糖核糖核酸链形成新的病毒颗粒。如果此组装过程中断，病毒将无法 产生复制能力强的病毒粒子并离开宿主细胞，从而抑制病毒的最后阶段 复制。考虑到这些考虑，SL3NCP7RNA-NCp7复合体已成为下一步- 新一代抗逆转录病毒药物。 寻找选择性地抑制SL3NCP7相互作用的分子遵循了几条路线 接近的方式。一种很有希望的方法是使用多肽。为此，合成了六肽(HKWPWW； Hp1)最近被描述为与RNA的SL3四环具有高亲和力，破坏了 NCp7，并在体外抑制HIV-1的复制。虽然这是药物开发的一个有希望的领先者，但 Hp1识别和结合sL3-核糖核酸的机制仍不明确。我们的目标是审问 高通量氨基酸多样化方法研究Hp1与核糖核酸结合的构效关系 (将HP1中的关键残基替换为非蛋白产生的变体)，同时进行计算机建模。从这些 洞察，优化HP1的结构以增强其与RNA的结合亲和力将作为当代的 开发一类新的HIV-1复制抑制剂的战略。