Structurally dissecting APOBEC3's for HIV-1 restriction

结构剖析 APOBEC3 的 HIV-1 限制

• 批准号: 9769778
• 负责人: Celia A. Schiffer
• 金额: $ 58.24万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769778
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Address; Adherence; Antiviral Agents; Arginine; Binding; Biological Assay; Biophysics; Buffers; Complement; Complex; Crystallization; Cullin 5 Protein; Cytidine; Cytidine Deaminase; Cytosine; DNA; DNA Binding; Data; Deaminase; Deamination; Drug Targeting; Drug resistance; Enzymatic Biochemistry; Enzymes; Epidemic; Epitopes; Family; Future; Goals; HIV; HIV Genome; HIV Infections; HIV vaccine; HIV-1; Homology Modeling; Human; Laboratories; Life Cycle Stages; Life Expectancy; Mediating; Methods; Modeling; Molecular; Molecular Mimicry; Mutate; Nucleic Acids; Patients; Pharmaceutical Preparations; Quality of life; RNA; RNA Binding; Roentgen Rays; Role; Series; Single-Stranded DNA; Site; Specificity; Structural Models; Structure; Substrate Specificity; Surface; Techniques; Therapeutic; Viral; Virus Diseases; X-Ray Crystallography; Zinc; base; elongin; improved; insight; interdisciplinary approach; novel; prevent; public health relevance; structural biology; targeted treatment; therapeutic development; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): As the worldwide AIDS epidemic begins its fourth decade, with ~34 million people living with HIV-AIDS around the globe, a cure or vaccine for HIV-1 still eludes us. Fortunately over 30 drugs that belong to seven classes targeting various stages in the life cycle of HIV have improved the overall quality and life expectancy of HIV-infected patients. To date, the most successful anti-viral HIV drugs abrogate functions of HIV enzymes. However, viral diversity from varied clades or poor adherence has led to the emergence of drug resistance preventing the therapeutic control of many HIV infections, warranting the identification of novel targets and therapeutic strategies. Our long-term goal is to develop new, complementary, anti-viral strategies by activating the natural anti-HIV functions of human restriction factors. The APOBEC3 (A3) family of single and double domain cytidine deaminases, particularly A3G, are critical enzymes in this restriction and whose molecular mechanisms may be leveraged in developing such host activated therapeutic strategies. We hypothesize that the molecular interactions and differential specificities of A3s to nucleic acids and HIV-1 Vif provide epitopes that once characterized will provide target sites for future therapeutic development.

 描述（由申请人提供）：随着全球艾滋病流行进入第四个十年，全球约有 3400 万艾滋病毒/艾滋病患者，幸运的是，我们仍然无法找到针对 HIV-1 的治疗方法或疫苗。针对艾滋病毒生命周期不同阶段的七类药物改善了艾滋病毒感染者的整体质量和预期寿命。迄今为止，最成功的抗艾滋病病毒药物消除了艾滋病毒酶的功能。进化枝或依从性差导致耐药性的出现，阻碍了许多艾滋病毒感染的治疗控制，需要确定新的靶点和治疗策略，我们的长期目标是 通过激活人类限制因子的天然抗 HIV 功能，开发新的、互补的抗病毒策略。我们追求 A3 与核酸和 HIV-1 Vif 的分子相互作用和差异特异性提供表位，一旦表征，将为未来的治疗开发提供靶位点。