Threading polyintercalators represent a potentially powerful method to control gene expression. Our laboratory has developed such molecules with naphthalene diimide (NDI) intercalating units connected head to tail by peptide linkers, which alternately bind in the major or minor groove. Optimization of these linkers has led to a tetraintercalating molecule with a dissociation half-life of 59 days; extending the number of intercalating units gave a hexaintercalating molecule with a 22bp binding site. A library search led to one major groove and one minor groove binding linker that together formed the basis for the successful molecules described above. Interestingly, the linker found to reside in the minor groove was the only member composed entirely of β-amino acids. In order to expand our repertoire of specific linkers, a library of bisintercalators with varied β-amino acid peptide linkers was synthesized and analyzed by DNase I footprinting for specific binding capability. Groove-binding preference was investigated by NMR spectroscopy.

Synthesis and screening of a β amino acid bisintercalator library

255th National Meeting (2018)

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