Structurally dissecting APOBEC3's for HIV-1 restriction

结构剖析 APOBEC3 的 HIV-1 限制

• 批准号: 9340247
• 负责人: Celia A. Schiffer
• 金额: $ 59.25万
• 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/9340247
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Address; Adherence; 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; Genome; Goals; HIV; 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; 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，地球仪约有3400万人患有HIV-艾滋病，我们仍然没有找到HIV-1的治愈方法或疫苗。幸运的是，针对艾滋病毒生命周期不同阶段的七类30多种药物提高了艾滋病毒感染者的总体质量和预期寿命。迄今为止，最成功的抗病毒HIV药物消除了HIV酶的功能。然而，来自不同进化枝的病毒多样性或粘附性差导致了耐药性的出现，阻止了许多HIV感染的治疗控制，阻碍了新靶标和治疗策略的鉴定。我们的长期目标是 通过激活人类限制性因子的天然抗HIV功能，开发新的、互补的抗病毒策略。单和双结构域胞苷脱氨酶的APOBEC 3（A3）家族，特别是A3 G，是这种限制中的关键酶，并且其分子机制可以在开发这种宿主激活的治疗策略中被利用。我们假设A3对核酸和HIV-1 Vif的分子相互作用和差异特异性提供了表位，这些表位一旦表征将为未来的治疗开发提供靶位点。