Development of compounds that recognize double-stranded DNA (dsDNA) in a sequence-specific manner is a research area, which is motivated by the prospect for molecular tools that can detect, regulate and modify genes. Significant advances have been made with triplex-forming oligonucleotides, peptide nucleic acids (PNAs), polyamides, pseudo-complementary PNA, gamma PNA and engineered proteins, among other approaches. However, given the restrictions of the current approaches, development of alternative strategies for specific mixed-sequence recognition of dsDNA at physiological conditions remains a highly desirable goal.Our laboratory is exploring Invaders, i.e., double-stranded oligonucleotide probes that are activated for dsDNA-recognition through modification with interstrand zipper arrangements of intercalator-functionalized monomers based on 2'-amino-alpha-L-LNA, 2'-N-methyl-2'-amino-DNA or RNA scaffolds. We have recently demonstrated that the stability difference between Invader probes and probe-target complexes can be used to drive mixed-sequence recognition of linear dsDNA targets, ii) DNA hairpins and iii) chromosomal DNA.1-3In this presentation, I will outline the Invader concept, discuss structure-property relationships and disclose results from biological dsDNA-recognition experiments. The results suggest that previously inaccessible DNA targets may become available to exogenous control, which has exciting implications for karyotyping, in vivo imaging, and gene regulation.ReferencesDidion, B. A.; Karmakar, S.; Guenther, D. C.; Sau, S. P.; Verstegen, J. P.; Hrdlicka, P. J. ChemBioChem, 2013  , 14, 1534-1538.Sau, S. P.; Madsen, A. S.; Podbevsek, P.; Andersen, N. K.; Kumar, T. S.; Andersen, S.; Rathje, R. L.; Anderson, B. A.; Guenther, D. C.; Karmakar, S.; Kumar, P.; Plavec, J.; Wengel, J.; Hrdlicka, P. J. J. Org. Chem., 2013  , 78, 9560-9570.Denn, B.; Karmakar, S.; Guenther, D. C.; Hrdlicka, P. J. Chem. Commun., 2013  , 49, 9851-9853.

Invaders: Recognition of double-stranded DNA using oligonucleotide duplexes with interstrand zippers of intercalator-functionalized nucleotides

247th National Meeting (2014)

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