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.

项目摘要 自1980年代初首次认可以来，艾滋病毒在全球享有超过3200万人的生命。前 在1990年代引入抗逆转录病毒疗法，感染HIV的个体可以发展为AIDS 艾滋病毒感染的最先进阶段，最致命的（诊断后约11个月生存）非常迅速。 但是今天，通过早期治疗，一个被诊断出患有艾滋病毒的人几乎可以与没有人相比 疾病。不幸的是，艾滋病毒无法治愈。更令人不安的是，目前挽救生命的抗逆转录病毒的曲目 阻止艾滋病毒感染的药物正在失去对感染的控制。在过去的十年中，病人很差 合规性（跳过每日抗逆转录病毒剂量）与环境因素相结合导致突变 导致耐药菌株的HIV病毒。现在比以往任何时候都多，攻击新病毒靶标的新疗法 迫切需要打击全球艾滋病毒大流行。 像所有病毒一样，HIV-1的生命周期依赖于宿主细胞机制。病毒感染CD4+ T淋巴细胞 （白细胞的特定群体）并使用细胞复制病毒基因组，组装新病毒 颗粒和释放病毒的副本，以感染更多的CD4+ T淋巴细胞。新病毒的形成 仅当在细胞内的其他RNA中鉴定出病毒RNA的情况，才能发生颗粒 成功招募到插科打综合体。这个基本的认可和招聘过程已完成 简而 RNA（称为RNA），位于病毒RNA链的茎环3（SL3）上，然后有助于包装 将RNA链收集到新的病毒颗粒中。如果此组装过程中断，病毒将无法 产生复制能力的病毒并退出宿主细胞，从而抑制病毒的最后阶段 复制。考虑到这些考虑，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。 选择性地抑制SL3RNA-NCP7相互作用的分子的追求已遵循了几行 方法。一个承诺的大道是使用Petides。为此，合成的六肽（hkwpww; 最近描述了HP1），显示了对rna的Sl3四折的高亲和力，破坏了结合的结合 NCP7并导致体外抑制HIV-1复制。虽然有前途的药物开发领导者，但 HP1识别并与SL3-RNA结合的机制仍然不确定。我们的目标是审问 HP1使用高通量氨基酸多样化与RNA结合的结构活性关系 （替换键保留在HP1中，以作为非蛋白质生成变体）与计算机建模中的同时。从这些 洞察力，HP1的结构优化以增强其与RNA的结合亲和力，将作为当代探索 开发新的HIV-1复制抑制剂的策略。