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Thioamide‐Bridged Nucleic Acid (thioAmNA) Containing Thymine or 2‐Thiothymine: Duplex‐Forming Ability, Base Discrimination, and Enzymatic Stability
Author(s) -
Habuchi Takaki,
Yamaguchi Takao,
Obika Satoshi
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800702
Subject(s) - oligonucleotide , nucleic acid , phosphodiester bond , thymine , chemistry , duplex (building) , deoxyribozyme , dna , rna , biochemistry , stereochemistry , combinatorial chemistry , nucleotide , enzyme , thioamide , gene
Oligonucleotides containing bridged nucleic acids (BNAs) show high duplex‐forming ability towards target single‐stranded RNA, so many BNAs have been developed for antisense applications. Amide‐bridged nucleic acids (AmNAs), which are BNA analogues bearing an amide bond at the bridge, exhibit high duplex‐forming ability, enzymatic stability, and antisense activity; thus, the AmNA motif represents a promising BNA scaffold. The high enzymatic stability of the AmNA motif is presumably attributable to the bulky amide structure, because it inhibits the access of nucleases to the phosphodiester linkage. Here, to improve enzymatic stability further, we designed thioAmNAs: thioamide‐bridged nucleotides that have a bulkier bridge structure than AmNA. The synthesis of thioAmNAs bearing either thymine (thioAmNA‐T) or 2‐thiothymine (thioAmNA‐S 2 T) bases was successful, and the obtained monomers were introduced into designed oligonucleotides without noticeable by‐product generation. The thioAmNA‐T‐ and thioAmNA‐S 2 T‐modified oligonucleotides showed strong binding affinity toward complementary single‐stranded RNA, with the thioAmNA‐S 2 T‐modified oligonucleotide displaying excellent base‐discrimination capability. Moreover, both thioAmNA‐T and thioAmNA‐S 2 T endowed oligonucleotides with higher resistance to enzymatic degradation than AmNA‐T. These results indicate that thioAmNAs are potentially useful chemical modifications for oligonucleotide‐based therapeutics.