Synthesis and Characterization of Conformationally-Preorganized MiniPEG-Containing γPNAs with Superior Hybridization Properties and Water Solubility

摘要

Developed in the early 1990's, PNA has emerged as a promising class of nucleic acid mimic because of its strong binding affinity and sequence selectivity towards DNA and RNA, and resistance to enzymatic degradation by proteases and nucleases; however, the main drawbacks, as compared to other classes of oligonucleotides, are water solubility and biocompatibility. Herein we show that installation of a relatively small, hydrophilic (R)-diethylene glycol (`miniPEG') unit at the γ-backbone transforms a randomly-folded PNA into a right-handed helix. Synthesis of optically pure ^R-MPγPNA monomers is described, which can be accomplished in a few simple steps from a commercially available and relatively cheap Boc-L-serine. Once synthesized, ^R-MPγPNA oligomers are preorganized into a right-handed helix and hybridize to DNA and RNA with greater affinity and sequence selectivity, and are more water soluble and less aggregating than the parental PNA oligomers. The results presented herein have important implications for the future design and application of PNA in biology, biotechnology and medicine, as well as in other disciplines including drug discovery and molecular engineering.