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Biochemistry. 2018 Apr 10;57(14):2094-2108. doi: 10.1021/acs.biochem.8b00062. Epub 2018 Mar 27.

Design of Bivalent Nucleic Acid Ligands for Recognition of RNA-Repeated Expansion Associated with Huntington's Disease.

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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.


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.

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