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Biol Chem. 1998 Aug-Sep;379(8-9):1045-52.

Peptide nucleic acids (PNA) and PNA-DNA chimeras: from high binding affinity towards biological function.

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1
Hoechst Marion Roussel Deutschland GmbH, Frankfurt am Main, Germany.

Abstract

Oligonucleotide analogs are of major interest as tools in molecular biology, as diagnostics, and as potential pharmaceuticals which bind in a predictable way to certain nucleic acid target sequences, aiming at the inhibition of expression of disease-causing genes. One of the most promising nucleic acid mimetics are the peptide - or polyamide- nucleic acids (PNA) which bind with higher affinity to DNA and RNA than natural oligonucleotides. In these non-ionic PNAs, the entire sugar-phosphate backbone is replaced by an N-aminoethylglycine-based polyamide structure. A unique property of PNA is its ability to displace one strand of a DNA double-helix. This strand displacement process, which is inefficient with DNA, is supported by the formation of an unusually stable internal (PNA)2 x DNA triple helix. The combination of PNA and DNA in one molecule results in PNA/DNA chimeras with new properties. They show improved aqueous solubility compared to pure PNAs due to their partially negatively charged structure. Furthermore, the cellular uptake of the chimeras is better than of pure PNAs. In contrast to PNA, the chimeras bind exclusively in the antiparallel orientation under physiological conditions. The binding affinity is generally stronger when the PNA/DNA chimeras are hybridized to RNAthan to DNA, whereby the strength of binding strongly depends on the PNA: DNA ratio. Most interestingly, PNA/DNA chimeras are recognized as substrates by various nucleic acid processing enzymes, and consequently can also assume biological functions, such as a primer function for DNA polymerases. Pure PNA cannot induce RNase H cleavage of target RNA, which is believed to support the biological efficacy of antisense agents. However, DNA-PNA chimeras are able to stimulate cleavage of the target RNA by RNase H upon formation of an RNA x chimera duplex.

PMID:
9792437
[Indexed for MEDLINE]
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