Hybridization and Mismatch Discrimination Abilities of 2′,4′-Bridged Nucleic Acids Bearing 2‑Thiothymine or 2‑Selenothymine Nucleobase

Oligonucleotides
modified with 2′-O,4′-C-spirocyclopropylene-bridged nucleic acid (scpBNA) exhibit
excellent duplex-forming ability with their complementary single-stranded
RNA (ssRNA). Here, we demonstrate that scpBNA bearing a 2-thiothymine
(scpBNA-S2T) or 2-selenothymine (scpBNA-Se2T)
nucleobase provides robust mismatch discrimination capabilities to
oligonucleotides without compromising their high binding affinities
toward the full complementary ssRNA. X-ray crystallographic analysis
of a self-assembling oligonucleotide featuring 2′,4′-BNA/LNA-2-thiothymine
(2′,4′-BNA/LNA-S2T, where 2′,4′-BNA
and LNA stand for “2′-O,4′-C-methylene-bridged nucleic acid” and “locked
nucleic acid”, respectively), a prototype of scpBNA-S2T, revealed that the 2-thiocarbonyl moiety plays a crucial role in
the destabilization of thymine–guanine mismatched wobble base
pairs.