Design of Bivalent Nucleic Acid Ligands for Recognition of RNA-Repeated Expansion Associated with Huntington's Disease.
Design of Bivalent Nucleic Acid Ligands for Recognition of RNA-Repeated Expansion Associated with Huntington's Disease.
复制标题
用于识别与亨廷顿病相关的 RNA 重复扩增的二价核酸配体的设计。
DOI：
10.1021/acs.biochem.8b00062
复制
发表时间：
2018
期刊：
影响因子：
2.9
通讯作者：
Ly,DanithH
中科院分区：
文献类型：
--
作者：
Thadke,ShivajiA;Perera,JDinithiR;Hridya,VM;Bhatt,Kirti;Shaikh,AshifY;Hsieh,Wei-Che;Chen,Mengshen;Gayathri,Chakicherla;Gil,RobertoR;Rule,GordonS;Mukherjee,Arnab;Thornton,CharlesA;Ly,DanithH
我们报道了一类新的核酸配体的开发，该配体由Janus碱基和MPγPNA骨架组成，并且能够通过推断二价氢键相互作用以序列特异性和选择性的方式结合rCAG重复序列。单独地，配体和RNA之间的相互作用是弱的和短暂的。然而，在C-末端硫酯和N-末端胱氨酸的安装和二硫键的还原后，它们经历模板指导的天然化学连接以形成紧密结合RNA模板的串联寡聚产物。在没有RNA靶点的情况下，它们通过分子内反应形成环状产物而自我失活，使它们对进一步结合无活性。这项工作对设计超短核酸配体具有重要意义，这些配体用于靶向与亨廷顿病和许多其他相关的神经肌肉和神经退行性疾病相关的rCAG重复扩增。
We report the development of a new class of nucleic acid ligands that is comprised of Janus bases and the MPγPNA backbone and is capable of binding rCAG repeats in a sequence-specific and selective manner via, inference, bivalent H-bonding interactions. Individually, the interactions between ligands and RNA are weak and transient. However, upon the installation of a C-terminal thioester and an N-terminal cystine and the reduction of disulfide bond, they undergo template-directed native chemical ligation to form concatenated oligomeric products that bind tightly to the RNA template. In the absence of an RNA target, they self-deactivate by undergoing an intramolecular reaction to form cyclic products, rendering them inactive for further binding. The work has implications for the design of ultrashort nucleic acid ligands for targeting rCAG-repeat expansion associated with Huntington’s disease and a number of other related neuromuscular and neurodegenerative disorders.