Mixed up minor groove binders: Convincing A·T specific compounds to recognize a G·C base pair

Nanjunda, Rupesh; Kumar, Arvind; Laughlin, Sarah; Nhili, Raja; Depauw, Sabine; Deuser, Shelby Sheldon; Chai, Yun; Chaudhary, Arpana S.; David-Cordonnier, Marie-Hélène; Boykin, David W.

doi:10.1016/j.bmcl.2015.05.005

Cited by 23 publications

(38 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surprisingly, the pyridyl linked ABP molecules bind as 2:1 cooperative dimers with the AATTGCAATT sequence (Table 3 and Supporting Information, Figure 5). The SPR results are given in Table 3, Figure 3, and Figure 5 along with the previously published DB2120 results for comparison (31). …”

Section: Resultsmentioning

confidence: 98%

“…General syntheses of new compounds (DB2146, DB2295, DB2150, DB2149, DB2355, DB2201, DB2302, DB2291, DB2300, DB2301, DB2298, DB2299, DB2314 and DB2315) are described in the Experimental Section and Supplementary Material. The syntheses of DB2114, DB2119 and DB2120 have been previously reported (26, 31). …”

Section: Resultsmentioning

confidence: 99%

“…The essential breakthrough in developing strong and selective single G·C bp recognition in this series was achieved with the pyridyl derivative of DB2119, DB2120 (31). In our initial report, it was observed that a phenyl (DB2119) to pyridyl (DB2120) change resulted in a striking increase in the thermal stability of the single G·C bp containing A4GT4 motif.…”

Section: Resultsmentioning

confidence: 99%

“…Because of their synthetic accessibility (25, 26), favorable cell uptake (7, 9), demonstrated clinical activity (27–29), and excellent solution properties (30), our initial design efforts for new types of mixed-sequence DNA binding compounds have focused on heterocyclic cations (26, 31, 32). One design concept includes three parts, two AT sequence recognition modules that flank a central G·C bp recognition unit.…”

Section: Introductionmentioning

confidence: 99%

“…This is a common sequence in the mitochondrial kinetoplast DNA of a number of parasitic organisms as well as in human gene promoter sequences (33, 34). We recently reported that DB2120 with a central pyridine linker unit flanked by phenyl-benzimidazole-based modules for AT recognition (Figure 1) could strongly and selectively recognize a single G base in a G·C bp flanked by AT sequences with an nM affinity (31). It is an important new design finding and complements other new minor groove binders that can also target mixed sequences of DNA (35, 36).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Systematic synthetic and biophysical development of mixed sequence DNA binding agents

et al. 2017

Self Cite

View full text Add to dashboard Cite

It is now well established that, although only about 5% of the human genome codes for protein, most of the DNA has some function, such as synthesis of specific, functional RNAs and/or control of gene expression. These functional sequences open immense possibilities in both biotechnology and therapeutics for the use of cell-permeable, small molecules that can bind mixed-base pair sequences of DNA for regulation of genomic functions. Unfortunately very few types of modules have been designed to recognize mixed DNA sequences and for progress in targeting specific genes, it is essential to have additional classes of compounds. Compounds that can be rationally designed from established modules and which can bind strongly to mixed base pair DNA sequences are especially attractive. Based on extensive experience in design of minor-groove agents for AT recognition, a small library of compounds with two AT specific binding modules, connected through linkers which can recognize the G·C base pairs, were prepared. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that some pyridyl-linked compounds bind with the target sequence with sub-nanomolar KD, with very slow dissociation kinetics and 200 times selectivity over the related sequence without a G·C base pair. Interestingly, a set of compounds with AT module connected by different linkers shows cooperative dimer recognition of related sequences. This type of design approach can be expanded to additional modules for recognition of a wide variety of sequences.

show abstract

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Systematic synthetic and biophysical development of mixed sequence DNA binding agents

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

DNA‐Binding Properties of New Fluorescent AzaHx Amides: Methoxypyridylazabenzimidazolepyrroleimidazole/pyrrole

et al. 2018

Self Cite

View full text Add to dashboard Cite

DNA minor groove binding polyamides have been extensively developed to control abnormal gene expression. The establishment of novel, inherently fluorescent 2-(p-anisyl)benzimidazole (Hx) amides has provided an alternative path for studying DNA binding in cells by direct observation of cell localization. Because of the 2:1 antiparallel stacking homodimer binding mode of these molecules to DNA, modification of Hx amides to 2-(p-anisyl)-4-azabenzimidazole (AzaHx) amides has successfully extended the DNA-recognition repertoire from central CG [recognized by Hx-I (I=N-methylimidazole)] to central GC [recognized by AzaHx-P (P=N-methylpyrrole)] recognition. For potential targeting of two consecutive GG bases, modification of the AzaHx moiety to 2- and 3-pyridyl-aza-benzimidazole (Pyr-AzaHx) moieties was explored. The newly designed molecules are also small-sized, fluorescent amides with the Pyr-AzaHx moiety connected to two conventional five-membered heterocycles. Complementary biophysical methods were performed to investigate the DNA-binding properties of these molecules. The results showed that neither 3-Pyr-AzaHx nor 2-Pyr-AzaHx was able to mimic I-I=N-methylimidazole-N-methylimidazole to target GG dinucleotides specifically. Rather, 3-Pyr-AzaHx was found to function like AzaHx, f-I (f=formamide), or P-I as an antiparallel stacked dimer. 3-Pyr-AzaHx-PI (2) binds 5'-ACGCGT'-3' with improved binding affinity and high sequence specificity in comparison to its parent molecule AzaHx-PI (1). However, 2-Pyr-AzaHx is detrimental to DNA binding because of an unfavorable steric clash upon stacking in the minor groove.

show abstract

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

Guo

Kumar

Farahat

et al. 2016

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

In spite of its importance in cell function, targeting DNA is under-represented in the design of small molecules. A barrier to progress in this area is the lack of a variety of modules that recognize G•C base pairs (bp) in DNA sequences. To overcome this barrier an entirely new design concept for modules that can bind to mixed GC and AT sequences of DNA is reported. Because of their successes in biological applications, minor-groove-binding heterocyclic cations were selected as the platform for design. Binding to AT sequences requires H-bond donors while recognition of the G-NH2 requires an acceptor. The concept that we report here uses preorganized N-methylbenzimidazole (N-MeBI) thiophene modules for selective binding with mixed bp DNA sequences. The interaction between the thiophene sigma-hole (positive electrostatic potential) and electron donor nitrogen of N-MeBI preorganizes the conformation for accepting an H-bond from G-NH2. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that N-MeBI-thiophene monomer compounds can strongly and selectively recognize single G•C bp sequences. Replacing the thiophene with other moieties significantly reduces binding affinity and specificity, as predicted by the design concept. These results show that the use of molecular features, such as sigma-hole, can lead to new approaches for small molecules in biomolecular interactions.

show abstract

Mixed up minor groove binders: Convincing A·T specific compounds to recognize a G·C base pair

Cited by 23 publications

References 41 publications

Systematic synthetic and biophysical development of mixed sequence DNA binding agents

Systematic synthetic and biophysical development of mixed sequence DNA binding agents

DNA‐Binding Properties of New Fluorescent AzaHx Amides: Methoxypyridylazabenzimidazolepyrroleimidazole/pyrrole

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

Contact Info

Product

Resources

About