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: 10460252
• 负责人: Steven Bloom
• 金额: $ 8.77万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460252
• 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-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; 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.

项目摘要 自1980年代初首次发现以来，艾滋病毒已在全世界夺去了3 200多万人的生命。之前 在20世纪90年代引入抗逆转录病毒疗法后，感染艾滋病毒的个体可能会发展为艾滋病， HIV感染的最晚期和最致命的阶段（诊断后约11个月的生存期）非常迅速。 但是今天，通过早期治疗，一个被诊断为艾滋病毒感染者可以活得几乎和一个没有艾滋病毒感染者一样长。 疾病不幸的是，没有治愈艾滋病毒的方法。更令人不安的是，目前挽救生命的抗逆转录病毒药物 控制艾滋病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（跳过每日抗逆转录病毒剂量）与环境因素相结合，导致了基因突变， 导致抗药性病毒株的HIV病毒。现在比以往任何时候都更需要攻击新病毒靶点的新疗法 是抗击全球艾滋病流行的迫切需要。 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CD 4 + T淋巴细胞 （一个特定的白色血细胞群体），并使用该细胞复制病毒基因组，组装新的病毒 颗粒，并释放病毒的副本感染更多的CD 4 + T淋巴细胞。新病毒的形成 只有当病毒RNA在细胞内大量的其他RNA中被鉴定出来时， 被成功招募到加格综合体这一重要的认可和招聘过程已经完成， 核衣壳蛋白（NCp 7）。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（SL 3）上，然后帮助包装病毒RNA。 收集RNA链形成新的病毒颗粒。如果这个组装过程被中断，病毒将无法 以产生有复制能力的病毒体并离开宿主细胞，从而抑制病毒的最后阶段， 复制的考虑到这些因素，SL 3 RNA-NCp 7复合物已成为下一个研究的主要靶点。 一代抗逆转录病毒药物。 对选择性抑制SL 3 β RNA-NCp 7相互作用的分子的探索遵循几条路线 的方法。一个有希望的途径是使用肽。为此，合成六肽（HKWPWW; HP 1）最近被描述，其显示出对HLA-RNA的SL 3四环的高亲和力，破坏了HLA-RNA的结合。 NCp 7并在体外抑制HIV-1复制。虽然是药物开发的一个有希望的领导， HP 1识别并结合SL 3-siRNA的机制仍然不清楚。我们的目标是审问 利用高通量氨基酸多样化研究HP 1与mRNA结合的构效关系 （用HP 1中的关键残基取代非蛋白原变体）与计算机建模串联。从这些 的见解，HP 1的结构优化，以提高其结合的亲和力，以RNA将探讨作为当代 开发一类新的HIV-1复制抑制剂的战略。