Thadke Shivaji A, Perera J Dinithi R, Hridya V M, Bhatt Kirti, Shaikh Ashif Y, Hsieh Wei-Che, Chen Mengshen, Gayathri Chakicherla, Gil Roberto R, Rule Gordon S, Mukherjee Arnab, Thornton Charles A, Ly Danith H
Department of Chemistry , Indian Institute of Science Education and Research (IISER) , Pune , Maharashtra 411008 , India.
Department of Neurology , Box 645, University of Rochester Medical Center , 601 Elmwood Avenue , Rochester , New York 14642 , United States.
Biochemistry. 2018 Apr 10;57(14):2094-2108. doi: 10.1021/acs.biochem.8b00062. Epub 2018 Mar 27.
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.
我们报道了一类新型核酸配体的开发，其由双功能碱基和MPγPNA骨架组成，能够通过推测的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。单独来看，配体与RNA之间的相互作用微弱且短暂。然而，在安装C端硫酯和N端胱氨酸并还原二硫键后，它们会经历模板导向的天然化学连接，形成紧密结合RNA模板的串联寡聚产物。在没有RNA靶标的情况下，它们会通过分子内反应自我失活，形成环状产物，从而使其失去进一步结合的活性。这项工作对设计用于靶向与亨廷顿舞蹈病以及许多其他相关神经肌肉和神经退行性疾病相关的rCAG重复序列扩增的超短核酸配体具有重要意义。
