A highly constrained nucleic acid analog based on α-l-threosamine.

Chemically modified oligonucleotides (ONs) have recently gained much attention as therapeutic materials because of their improved properties. Here, a newly designed nucleic acid analog based on α-l-threosamine (named cTNA) is reported. cTNA has a "dual" constrained structure, with a bridged sugar moiety and shorter phosphoramidate backbone, to reduce the entropy loss during the hybridization. Unexpectedly, ONs containing the cTNA unit showed lower binding affinity with complementary RNA and DNA than natural ONs. Quantum chemical calculations imply that the relative nucleobase orientation of cTNA may be unfavorable for hybridization.