A novel triazole linkage that mimics the phosphodiester backbone in DNA was designed, synthesised and evaluated. Unlike previous work which utilised copper to form a 1,4 triazole linkage in the DNA backbone, a ruthenium catalyst was used to yield a 1,5 triazole. The artificial linkage was incorporated into a DNA backbone via a phosphoramidite building block using solid phase synthesis. The biophysical properties of DNA with a 1,5 triazole linkage in the backbone were evaluated by UV melting and circular dichroism and compared to DNA modified with previously reported 1,4 triazole linkages of various lengths.

Triazole linkages (TLs) are mimics of the phosphodiester bond in oligonucleotides with applications in synthetic biology and biotechnology. Here we report the RuAAC-catalyzed synthesis of a novel 1,5-disubstituted triazole (TL 2 ) dinucleoside phosphoramidite as well as its incorporation into oligonucleotides and compare its DNA polymerase replication competency with other TL analogues. We demonstrate that TL 2 has superior replication kinetics to these analogues and is accurately replicated by polymerases. Derived structure–biocompatibility relationships show that linker length and the orientation of a hydrogen bond acceptor are critical and provide further guidance for the rational design of artificial biocompatible nucleic acid backbones.