PEPTIDE SHIELDED DNA COMPLEXES

描述：第一个提案的目标是开发肽屏蔽的 寡核苷酸作为保护基于核酸的治疗剂的手段 在分娩过程中。 第一个具体目标是设计化学合成， 肽，5-16个残基和核酸2-8个核苷酸之间的杂交， 为了提高生物利用度和稳定性， 寡核苷酸 选择了三类肽：SPKK （组蛋白尾）、PRGRP（HMG-I蛋白DNA结合结构域）、KWK基序 （单链选择性）和AAKK重复（已知增加 DNA杂交）。 具体目标二是选择具有以下特性的肽-DNA杂交体： 增加的靶亲和力和生物稳定性。 具体目标三和四 处理DNA-肽缀合物的结构研究。 UV和CD研究 将确定肽对DNA热力学稳定性的影响 单链和DNA双链体。 肽-DNA的NMR和X射线研究 还提出了共轭物。 该提案的第五个目的是将 肽-DNA缀合物的第三个功能是进一步增强细胞增殖， 例如融合肽序列。

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.