Autonomously Pairing Cysteinyl-Linked Nucleotide Analogues with a Unique Architecture

Abstract

We report the efficient pairing in water of the first representative of oligonucleotide analogues in which the backbone is replaced by linking elements between the nucleobases. The architecture of the new analogue demonstrates that the structural differentiation of oligonucleotides into a contiguous backbone and nucleobases, as embodied by the natural nucleic acids and all nucleotide analogues analyzed to date, is not a prerequisite for pairing. UV and circular dichroism analyses of self-complementary and non-self-complementary octanucleotide analogues strongly suggest the fully reversible, sequence-specific association of our new analogues to form a left-handed double helix with an antiparallel strand orientation that is characterized by melting temperatures and free enthalpies higher than those of natural RNA and DNA of the same sequence. The linking element incorporates an L-cysteine moiety that allows a short and efficient synthesis of the monomeric building blocks and, through the choice of either L- or D-cysteine, gives access to either one of the enantiomeric oligomers and thus to left- or right-handed helices.