SEQUENCE SPECIFIC RECOGNITION OF DNA

DNA 的序列特异性识别

• 批准号: 6125252
• 负责人: Peter B Dervan
• 金额: $ 26.55万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6125252
• 关键词: DNA; chemical binding; chemical structure function; imidazole; imidazole carboxamide; intermolecular interaction; nucleic acid sequence; nucleic acid structure; peptide analog; peptide chemical synthesis; pyrroles; synthetic peptide

The sequence specific recognition of double helical DNA is an essential biological process responsible for the regulation of cellular functions including transcription, replication, and cell division. The ability to design synthetic molecules that bind sequence specifically to unique sites on human DNA has major implications for the treatment of genetic, oncogenic and viral diseases. Basic research on structure-function issues such as recognition and covalent modification of DNA will be carried out. Research will focus on recognition of the minor groove of double helical DNA by a novel 2:1 peptide:DNA motif. Our specific objectives during the next four years are: (1) develop solid phase methods for the synthesis of oligopeptides containing imidazole and N-methylpyrrolecarboxamides. (2) define the sequence composition rules for recognition for the 2:1 peptide DNA motif by constructing and studying of the energetics of twenty-six different hairpin peptides. (3) define the upper limits for binding site size by the 2:1 motif. (4) design and study the energetics of binding of a novel class of alpha-amino acid linked imidazole-methylpyrrolecarboxamide peptides. (5) synthesize a class of rigid hairpin peptides and analyze the energetics for affinity and specificity. (6) synthesize a class of cyclic peptides and analyze the energetics for affinity and specificity. (7) develop a method for sequence specific DNA bending by the 2:1 DNA motif. (8) develop sequence specific ligation of double helical DNA promoted by minor groove binding prptides. In addition to the synthesis, specificity, and energetic studies at Caltech, all new synthetic peptides will be sent to UC Berkeley for structure elucidation of the peptide-DNA complexes by 2-D NMR.

双螺旋DNA的序列特异性识别是必不可少的 负责调节细胞功能的生物过程 包括转录、复制和细胞分裂。有能力 设计合成分子，将序列特异性地结合到独特的位置 对人类DNA的研究对遗传性、致癌性肿瘤的治疗具有重要意义 和病毒性疾病。关于结构功能等问题的基础研究 将对DNA进行识别和共价修饰。研究 将集中在识别双螺旋DNA的小凹槽上 新的2：1肽：DNA基序。我们在未来四年的具体目标 几年来：(1)开发固相合成方法 含咪唑和N-甲基吡咯甲酰胺的寡肽。(2) 定义识别2：1肽的序列组成规则 二十六能量学的构建和研究中的DNA基序 不同的发夹多肽。(3)确定结合部位上限 按2：1的图案大小。(4)设计和研究了胶束结合的能量学。 一类新的α-氨基酸连接咪唑-甲基吡咯甲酰胺 多肽。(5)合成了一类刚性发夹多肽并进行了分析。 关于亲和力和专一性的能量学。(6)合成一类 并对环肽的亲和力和特异性进行能量分析。 (7)建立了利用2：1 DNA进行序列特异性DNA弯曲的方法 Motif。(8)开展双螺旋DNA序列特异性连接 由次要沟槽结合多肽促进。除了合成之外， 加州理工学院的专一性和能量研究，所有新的合成肽 将被送往加州大学伯克利分校进行多肽-DNA的结构鉴定 通过二维核磁共振仪对化合物进行了表征。