Structurally dissecting APOBEC3's for HIV-1 restriction

结构剖析 APOBEC3 的 HIV-1 限制

• 批准号: 9080050
• 负责人: Celia A. Schiffer
• 金额: $ 61.42万
• 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/9080050
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Address; Adherence; Arginine; Binding; Biological Assay; Biophysics; Buffers; Complement; Complex; Cullin 5 Protein; Cytidine; Cytidine Deaminase; Cytosine; DNA; DNA Binding; Data; Deaminase; Deamination; Drug Targeting; Drug resistance; Enzymatic Biochemistry; Enzymes; Epidemic; Epitopes; Family; Figs - dietary; Future; Genome; Goals; HIV; HIV Infections; HIV-1; Homology Modeling; Human; Laboratories; Life; 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; Staging; Structure; Substrate Specificity; Surface; Techniques; Therapeutic; Vaccines; Viral; Virus Diseases; X-Ray Crystallography; Zinc; base; elongin; improved; insight; new therapeutic target; 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（由适用提供）：随着全球流行病开始其第四个十年，全球约有3400万人患有艾滋病毒艾滋病，艾滋病毒-1的治疗或疫苗仍然使我们避免。幸运的是，在艾滋病毒生命周期中，属于七个类别的七个类别的30多种药物改善了艾滋病毒感染患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，各种进化枝或依从性差的病毒多样性导致耐药性的出现，阻止了许多HIV感染的治疗控制，警告鉴定新的靶标和治疗策略。我们的长期目标是 通过激活人类限制因素的自然抗HIV功能来制定新的，完整的抗病毒策略。在这种限制中，单域和双域胞死亡蛋白（尤其是A3G）的APOBEC3（A3）家族是关键的酶，其分子机制可能会在开发这种宿主激活的治疗策略中利用。我们假设A3S对核酸和HIV-1 VIF的分子相互作用和差异规格提供了曾经表征的表位，将为未来的治疗发育提供目标位点。