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Designed compounds for recognition of 10 base pairs of DNA with two at binding sites.

ABSTRACT: Short AT base pair sequences that are separated by a small number of GCs are common in eukaryotic parasite genomes. Cell-permeable compounds that bind effectively and selectively to such sequences present an attractive therapeutic approach. Compounds with linked, one or two amidine-benzimidazole-phenyl (ABP) motifs were designed, synthesized, and evaluated for binding to adjacent AT sites by biosensor-surface plasmon resonance (SPR). A surprising feature of the linked ABP motifs is that a set of six similar compounds has three different minor groove binding modes with the target sequences. Compounds with one ABP bind independently to two separated AT sites. Unexpectedly, compounds with two ABP motifs can bind strongly either as monomers or as cooperative dimers to the full site. The results are supported by mass spectrometry and circular dichroism, and models to explain the different binding modes are presented.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3526804 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Designed compounds for recognition of 10 base pairs of DNA with two at binding sites.

Liu Yang Y Chai Yun Y Kumar Arvind A Tidwell Richard R RR Boykin David W DW Wilson W David WD

Journal of the American Chemical Society 20120309 11

Short AT base pair sequences that are separated by a small number of GCs are common in eukaryotic parasite genomes. Cell-permeable compounds that bind effectively and selectively to such sequences present an attractive therapeutic approach. Compounds with linked, one or two amidine-benzimidazole-phenyl (ABP) motifs were designed, synthesized, and evaluated for binding to adjacent AT sites by biosensor-surface plasmon resonance (SPR). A surprising feature of the linked ABP motifs is that a set of ...[more]

PMID: 22369366

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Project description:The solution structure of the complex formed between an oligodeoxynucleotide containing a two-base bulge (5'-CCATCGTCTACCTTTGGTAGGATGG) and SCA-alpha2, a designed spirocyclic helical molecule, has been elucidated. SCA-alpha2, a close mimic of the metabolite, NCSi-gb, of the DNA bulge-specific enediyne antibiotic neocarzinostatin, differs in possessing a more stable spirocyclic ring system and in lacking certain bulky groupings that compromise bulged DNA binding. This study provides a detailed comparison of the binding modes of the two complexes and provides new insights into the importance of shape and space, as opposed to simple nucleotide sequence, in complex formation at the bulge site. The two rigidly held aromatic rings of SCA-alpha2 form a right-handed helical molecular wedge that specifically penetrates the bulge-binding pocket and immobilizes the two bulge residues (GT), which point toward the minor groove, rather than the major groove as in the NCSi-gb.bulged DNA complex. The ligand aromatic ring systems stack on the DNA bulge-flanking base pairs that define the long sides of the triangular prism binding pocket. Like NCSi-gb, SCA-alpha2 possesses the natural N-methylfuranose moiety, alpha-linked to the benzindanol (BI) moiety. The amino sugar anchors in the major groove of the DNA and points toward the 3'-bulge-flanking base pair. Lacking the bulky cyclocarbonate of NCSi-gb, the SCA-alpha2.bulged DNA complex has a much less twisted and buckled 3'-bulge-flanking base pair (dG20.dC8), and the G20 residue stacks directly above the BI ring platform. Also, the absence of the methyl group and the free rotation of the methoxy group on the dihydronaphthanone (NA) moiety of SCA-alpha2 allow better stacking geometry of the NA ring above the 5'-bulge-flanking dG21.dC5 base pair. These and other considerations help to explain why NCSi-gb binds very poorly to bulged RNA and are consistent with the recent observation of good binding with SCA-alpha2. Thus, although the two complexes resemble each other closely, they differ in important local environmental details. SCA-alpha2 has a better hand-in-glove fit at the bulge site, making it an ideal platform for the placement of moieties that can react covalently with the DNA and for generating congeners specific for bulges in RNA.

Dataset Information

Designed compounds for recognition of 10 base pairs of DNA with two at binding sites.

Publications

Designed compounds for recognition of 10 base pairs of DNA with two at binding sites.

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