DESIGNER DNA BINDING PROTEINS TARGETING HIV GENES

针对 HIV 基因设计 DNA 结合蛋白

• 批准号: 2887325
• 负责人: ANDREW C JAMIESON
• 金额: $ 26.52万
• 依托单位: SANGAMO BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887325
• 关键词: DNA binding protein; antiAIDS agent; clinical research; drug screening /evaluation; human immunodeficiency virus 1; human subject; method development; tissue /cell culture; transfection; virus replication

Zinc fingers are a class of DNA binding proteins that can be designed to recognize DNA sequences according to a recently devised recognition code. This development has opened up the possibility of designing chimeric transcription respressors, transactivators and endonucleases for regulating or inactivating specific viral and human genes. we propose to utilize this emerging technology to develop drugs capable of inhibiting expression of an essential HIV gene. In Phase I, we constructed and characterized the binding affinities for three designer zinc finger proteins that target adjacent conserved, 9 base-pair sequences in an essential HIV gen. In Phase II, we will determine the ability of these proteins to bind HIV DNA sequences and attenuate growth of HIV in vivo. We will also link pairs of the zinc finger proteins with a peptide linker to construct hybrid DNA binding proteins with up to 18 base-pair specificity. This research will lead to the development of therapeutic drugs for attenuating viral reproduction. More generally, the development of designer DNA binding protein technology will lead to the development of novel therapeutics for treating a variety of viral and human diseases, including cancer, infectious diseases and autoimmune disorders. PROPOSED COMMERCIAL APPLICATION: The designer DNA binding proteins that we propose to develop will be an important proof-of-principle for a new class of anti-viral drugs. Their most immediate potential application is in the detection of viral DNA sequences for diagnostic proposes. the longer term potential therapeutic applications are to selectively inhibit viral gene expression within infected cells to help in reducing viral load.

锌指是一类可以设计的 DNA 结合蛋白 根据最近设计的识别方法来识别 DNA 序列 代码。这一发展开辟了设计的可能性 嵌合转录抑制因子、反式激活因子和核酸内切酶 用于调节或灭活特定病毒和人类基因。我们 提议利用这一新兴技术来开发能够 抑制 HIV 必需基因的表达。在第一阶段，我们 为三位设计师构建并表征了结合亲和力 靶向相邻保守的 9 个碱基对的锌指蛋白 HIV 必需基因中的序列。在第二阶段，我们将确定 这些蛋白质结合 HIV DNA 序列并减弱生长的能力 体内的艾滋病毒。我们还将把锌指蛋白对与 用于构建具有多达 18 个杂合 DNA 结合蛋白的肽接头 碱基对特异性。这项研究将促进以下领域的发展 用于减弱病毒繁殖的治疗药物。更一般地说， 设计DNA结合蛋白技术的发展将导致 开发治疗多种病毒的新疗法 和人类疾病，包括癌症、传染病和自身免疫性疾病 失调。 拟议的商业应用： 我们建议开发的设计 DNA 结合蛋白将是 一类新型抗病毒药物的重要原理验证。他们的 最直接的潜在应用是病毒 DNA 的检测 诊断建议的序列。长期潜在治疗 应用是选择性抑制病毒基因表达 受感染的细胞有助于减少病毒载量。