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

TY - JOUR

T1 - Design of Bivalent Nucleic Acid Ligands for Recognition of RNA-Repeated Expansion Associated with Huntington's Disease

AU - Thadke, Shivaji A.

AU - Perera, J. Dinithi R.

AU - Hridya, V. M.

AU - Bhatt, Kirti

AU - Shaikh, Ashif Y.

AU - Hsieh, Wei Che

AU - Chen, Mengshen

AU - Gayathri, Chakicherla

AU - Gil, Roberto R.

AU - Rule, Gordon S.

AU - Mukherjee, Arnab

AU - Thornton, Charles A.

AU - Ly, Danith H.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1021/acs.biochem.8b00062

DO - 10.1021/acs.biochem.8b00062

M3 - Journal article

C2 - 29562132

AN - SCOPUS:85045211380

SN - 0006-2960

VL - 57

SP - 2094

EP - 2108

JO - Biochemistry

JF - Biochemistry

IS - 14

ER -