Recognition of the four Watson–Crick base pairs in the DNA minor groove by synthetic ligands

Abstract

The design of synthetic ligands that read the information stored in the DNA double helix has been a long-standing goal at the interface of chemistry and biology. Cell-permeable small molecules that target predetermined DNA sequences offer a potential approach for the regulation of gene expression. Oligodeoxynucleotides that recognize the major groove of double-helical DNA via triple-helix formation bind to a broad range of sequences with high affinity and specificity. Although oligonucleotides and their analogues have been shown to interfere with gene expression, the triple-helix approach is limited to recognition of purines and suffers from poor cellular uptake. The subsequent development of pairing rules for minor-groove binding polyamides containing pyrrole (Py) and imidazole (Im) amino acids offers a second code to control sequence specificity. An Im/Py pair distinguishes G x C from C x G and both of these from A x T/T x A base pairs. A Py/Py pair specifies A,T from G,C but does not distinguish AT from T x A. To break this degeneracy, we have added a new aromatic amino acid, 3-hydroxypyrrole (Hp), to the repertoire to test for pairings that discriminate A x T from T x A. We find that replacement of a single hydrogen atom with a hydroxy group in a Hp/Py pairing regulates affinity and specificity by an order of magnitude. By incorporation of this third amino acid, hydroxypyrrole-imidazole-pyrrole polyamides form four ring-pairings (Im/Py, Py/Im, Hp/Py and Py/Hp) which distinguish all four Watson-Crick base pairs in the minor groove of DNA.

Interaction between a DNA oligonucleotide and a dinuclear iron(II) supramolecular cylinder; an NMR and molecular dynamics study

“…Snapshots of the 1.5 ns trajectory from the molecular dynamics simulation 2 ] system clearly shows that the cylinder has a dramatic influence on the conformation of the oligonucleotide (Fig. 6).…”

“…However, to date little progress has been made in this direction, due in large part to the size of the molecular surfaces required to achieve this. Indeed synthetic molecules that do achieve sequence selectivity, such as amide linked imidazole/ pyrrole oligomers which bind in the minor groove [2], are rare. Oligonucleotides (synthetic and natural) can selectively recognize DNA by forming triplexes through binding in the major groove [3] and neutral oligonucleotide analogues (e.g.…”

Direct detection of double-stranded DNA: molecular methods and applications for DNA diagnostics

“…2). 5,21,22 These seminal studies have allowed polyamides to emerge as a useful molecular recognition tool kit for sequence-specific targeting of dsDNA.…”

Sequence-specific DNA binding by long hairpin pyrrole–imidazole polyamides containing an 8-amino-3,6-dioxaoctanoic acid unit

“…An antiparallel pairing of Im opposite Py (Im/Py pair) distinguishes G-C from C-G, whereas a Py/Py pair binds both A-T and T-A base pairs. [1][2][3][4][5][6] PyIm polyamides have strong DNA binding affinity and sequence specificity for target match sequences. Various types of sequencespecific Py-Im polyamides have been developed to control gene expression by competitive binding against DNA-binding proteins such as transcription factor.…”