High Thermal Stability of 5'-5'-Linked Alternate Hoogsteen Triplexes at Physiological pH

摘要

Sequence-specific recognition, targeting, treatment, and alteration of double-stranded DNA (dsDNA) are topics of considerable interest for the study of mutated or recombined genes.[1] The formation of triple helixes through binding of a single-stranded triplex-forming oligonucleotide (TFO) to a homopurine sequence of dsDNA through major-groove interactions is one of the approaches to generate novel therapeutics on the dsDNA level. The design of a third strand that will bind to the dsDNA under physiological conditions is still challenging. In the parallel binding motif, the sensitivity of C+G-C Hoogsteen base pairs to pH must be overcome.[2] The formation of stable secondary structures, such as quadruplexes,[2], [3] and the instability of triplexes in the presence of K+ and Na+ ions are major limitations for purine-containing TFOs.[2], [4] Another limitation for the generation of a TFO is its length, which is supposed to be in the range of 15 to 30 base pairs to ensure target-specificity and binding affinity.