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Issue 9, 2010
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Invader LNA: Efficient targeting of short double stranded DNA

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Abstract

Despite progress with triplex-forming oligonucleotides or helix-invading peptide nucleic acids (PNAs), there remains a need for probes facilitating sequence-unrestricted targeting of double stranded DNA (dsDNA) at physiologically relevant conditions. Invader LNA probes, i.e., DNA duplexes with “+1 interstrand zipper arrangements” of intercalator-functionalized 2′-amino-α-L-LNA monomers, are demonstrated herein to recognize short mixed sequence dsDNA targets. This approach, like pseudo-complementary PNA (pcPNA), relies on relative differences in stability between probe duplexes and the corresponding probe:target duplexes for generation of a favourable thermodynamic gradient. Unlike pcPNA, Invader LNA probes take advantage of the “nearest neighbour exclusion principle”, i.e., intercalating units of Invader LNA monomers are poorly accommodated in probe duplexes but extraordinarily well tolerated in probe-target duplexes (ΔTm/modification up to +11.5 °C). Recognition of isosequential dsDNA-targets occurs: a) at experimental temperatures much lower than the thermal denaturation temperatures (Tm's) of Invader LNAs or dsDNA-targets, b) at a wide range of ionic strengths, and c) with good mismatch discrimination. Recognition of dsDNA is monitored in real-time using inherent pyrene–pyrene excimer signals of Invader LNA probes, which provides insights into reaction kinetics and enables rational design of probes. These properties render Invader LNAs as promising probes for biomedical applications entailing sequence-unrestricted recognition of dsDNA.

Graphical abstract: Invader LNA: Efficient targeting of short double stranded DNA

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Publication details

The article was received on 10 Nov 2009, accepted on 20 Jan 2010 and first published on 04 Mar 2010


Article type: Paper
DOI: 10.1039/B923465A
Citation: Org. Biomol. Chem., 2010,8, 2028-2036
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    Invader LNA: Efficient targeting of short double stranded DNA

    S. P. Sau, T. S. Kumar and P. J. Hrdlicka, Org. Biomol. Chem., 2010, 8, 2028
    DOI: 10.1039/B923465A

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