Completion of a programmable DNA-binding small molecule library

Hsu, Carey F.; Phillips, John W.; Trauger, John W.; Farkas, Michelle E.; Belitsky, Jason M.; Heckel, Alexander; Olenyuk, Bogdan; Puckett, James W.; Wang, Clay C. C.; Dervan, Peter B.

doi:10.1016/j.tet.2007.03.041

Cited by 65 publications

(85 citation statements)

References 54 publications

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“…In the present study, we designed and synthesized a cell-permeable, sequence-specific, DNA-binding polyamide SL-A92 to target the sequence CGG, which is the binding site of zinc cluster transcription factors, with the goal of interrupting some MDR gene expression and thus further inhibiting drug resistance. Just as reported previously [30] , we also found that SL-A92 had no cytotoxicity, as revealed by its antifungal activity and effects on strain growth. Based on the theory [31] of how polyamide exerts its function of gene regulation, a clinically isolated drug-resistant strain Y012 was incubated with SL-A92 for 20 days.…”

Section: Discussionsupporting

confidence: 89%

“…Small molecule approaches for gene regulation could bypass the need for delivery strategies. A number of natural and synthetic DNA binding molecules [30,31] . Sequence specificity is programmed by side-by-side pairings of the heterocyclic amino acids in the minor groove of DNA: Im/Py distinguishes GC from CG; Py/Py binds both AT and TA [32,33] .…”

Section: Introductionmentioning

confidence: 99%

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A novel polyamide SL-A92 as a potential fungal resistance blocker: synthesis and bioactivities in Candida albicans

et al. 2010

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Aim: To synthesize a novel polyamide SL-A92 and evaluate its bioactivity against drug resistance in Candida albicans. Methods: SL-A92 was synthesized using N-hydroxybenzotriazole (HOBT)/N,N'-dicyclohexylcarbodiimide (DCC) in solution phase. Its antifungal activities and effects on strain growth were tested using the micro-broth dilution method and growth curves, respectively. Induced drug resistance in the C. albicans collection strain SC5314 was obtained by incubation with fluconazole (12 μg/mL) for 21 passages. Meanwhile, incubations with SL-A92 plus fluconazole were also carried out in SC5314 strains, and the MIC 80 s were used to evaluate the inhibitory effects of SL-A92 on drug resistance during the induction process. Real time RT-PCR was performed to investigate the CDR1 and CDR2 mRNA levels in induced SC5314 strains. Results: SC5314 strain induced by the combination of fluconazole and SL-A92 (200 μg/mL) did not develop drug resistance. On day 24, the CDR1 and CDR2 mRNA levels in SC5314 strain co-treated with fluconazole and SL-A92 relative to fluconazole alone were 26% and 24%, respectively, and on day 30 the CDR1 and CDR2 mRNA levels were 43% and 31%, respectively. Conclusion: SL-A92 can block the development of drug resistance during the fluconazole induction process, which partially results from the down-regulation of CDR1 and CDR2.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

A novel polyamide SL-A92 as a potential fungal resistance blocker: synthesis and bioactivities in Candida albicans

et al. 2010

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“…Polyamides containing Nmethylimidazole (Im) and N-methylpyrrole (Py) comprise a class of programmable DNA-binding ligands capable of binding to a broad repertoire of DNA sequences with affinities and specificities comparable to those of natural DNA-binding proteins (17,18). Sequence specificity is programmed by side-by-side pairings of the heterocyclic amino acids in the minor groove of DNA: Im/Py distinguishes G⅐C from C⅐G; Py/Py binds both A⅐T and T⅐A (19,20).…”

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confidence: 99%

Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

Nickols

Dervan

2007

Proc. Natl. Acad. Sci. U.S.A.

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Androgen receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. A DNA-binding polyamide that targets the consensus androgen response element binds the prostate-specific antigen (PSA) promoter androgen response element, inhibits androgeninduced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity.prostate cancer ͉ bicalutamide ͉ small molecule ͉ transcription

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“…N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides are a class of programmable DNA-binding ligands capable of binding sequence specifically to DNA with affinities and specificities comparable to those of natural DNA-binding proteins (16,17). As oligomers composed of Im and Py heterocyclic rings, Py-Im polyamides achieve sequence specificity via side-by-side pairings of the heterocyclic amino acids in the minor groove of DNA: Im paired against Py distinguishes G⅐C from C⅐G, and Py paired against Py binds both A⅐T and T⅐A (18,19).…”

mentioning

confidence: 99%

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

Muzikar

Nickols²,

Dervan³

2009

Proc. Natl. Acad. Sci. U.S.A.

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The glucocorticoid receptor (GR) affects the transcription of genes involved in diverse processes, including energy metabolism and the immune response, through DNA-binding dependent and independent mechanisms. The DNA-binding dependent mechanism occurs by direct binding of GR to glucocorticoid response elements (GREs) at regulatory regions of target genes. The DNA-binding independent mechanism involves binding of GR to transcription factors and coactivators that, in turn, contact DNA. A small molecule that competes with GR for binding to GREs could be expected to affect the DNAdependent pathway selectively by interfering with the protein-DNA interface. We show that a DNA-binding polyamide that targets the consensus GRE sequence binds the glucocorticoid-induced zipper (GILZ) GRE, inhibits expression of GILZ and several other known GR target genes, and reduces GR occupancy at the GILZ promoter. Genome-wide expression analysis of the effects of this polyamide on a set of glucocorticoid-induced and -repressed genes could help to elucidate the mechanism of GR regulation for these genes.gene regulation ͉ glucocorticoid response element ͉ nuclear receptor ͉ protein-DNA interface ͉ Py-Im polyamide

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Completion of a programmable DNA-binding small molecule library

Cited by 65 publications

References 54 publications

A novel polyamide SL-A92 as a potential fungal resistance blocker: synthesis and bioactivities in Candida albicans

A novel polyamide SL-A92 as a potential fungal resistance blocker: synthesis and bioactivities in Candida albicans

Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

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