PEPTIDE SHIELDED DNA COMPLEXES

描述：第一个方案的目标是开发多肽屏蔽剂 寡核苷酸作为一种保护核酸类治疗药物的手段 在分娩过程中。第一个具体目标是设计化学合成，以 多肽、5-16个残基与2-8个核苷酸的杂交 用于提高生物利用度和稳定性的长度 寡核苷酸。我们选择了三类多肽：SPKK (组蛋白尾巴)、PRGRP(HMG-I蛋白DNA结合域)、KWK基序 (单链选择性)和AAKK重复(已知可增加 DNA杂交)。具体目标二是筛选具有以下特性的多肽-DNA杂交体 提高了靶标亲和力和生物稳定性。具体目标三和四 处理DNA-多肽结合物的结构研究。UV和CD研究 将决定多肽对DNA热力学稳定性的影响 单链和DNA双链。多肽-DNA的核磁共振和X射线研究 本文还提出了共轭化合物的概念。该提案的第五个目标是将一个 多肽-DNA结合物的第三个功能，进一步增强细胞 摄取，如融合多肽序列。

DESCRIPTION: The goal of this FIRST proposal is to develop peptide-shielded oligonucleotides as a means to protect nucleic acid-based therapeutic agents during delivery. The first specific aim is to design chemical syntheses for hybrids between peptides, 5-16 residues and nucleic acids 2-8 nucleotides in length for purposes of improving bioavailability and stability of the oligonucleotides. Three classes of peptides have been chosen: SPKK (histone tails), PRGRP (HMG-I protein DNA binding domain), the KWK motifs (single strand selective) and AAKK repeats (known to increase kinetics of DNA hybridization). Specific aim two is to select peptide-DNA hybrids with increased target affinity and biostability. Specific aims three and four deal with structural studies of DNA-peptide conjugates. UV and CD studies will determine the effect of peptide on thermodynamic stability of DNA single strand and DNA duplex. NMR and x-ray studies of peptide-DNA conjugates are also proposed. A fifth aim of the proposal is to link a third function to the peptide-DNA conjugate that further enhances cellular uptake such as a fusogenic peptide sequence.