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Synthetic progress in cMyc-Max oncoprotein miniaturization: semi-online monitoring gives solid-phase access to hydrophobic b(-HLH-)ZIP peptidosteroid tweezers

Dieter Verzele (UGent) and Annemieke Madder (UGent)
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Abstract
Miniature versions of basic leucine zipper (bZIP) and basic helix-loop-helix zipper (b-HLH-ZIP) transcription factors are promising tools for molecular dissection of the genetic information in a post-genomic context. Despite the opportunities of genome interfering agents based on certain oncogenic zipper proteins, structural mimicry of transcription factors is a delicate undertaking, and experimental fine-tuning through bottom-up organic chemistry could benefit from solid-phase/library approaches. Involved in a variety of human pathologies, we became interested in the miniaturization of the cMyc-Max b-HLH-ZIP oncoprotein, and herein elaborate on our synthetic progress in that direction. A bile acid scaffold was successfully employed as artificial dimerization interface in this new type of transcription factor model. Orthogonality of the applied Alloc/Boc/Fmoc chemistries allowed the synthesis of both homo-and heterodimeric peptidosteroid conjugates, covalently restricted with defined geometrical properties. Recognition peptides were assembled through standard Fmoc/tBu solid-phase peptide synthesis (SPPS) chemistry, assisted by automated procedures for consecutive chain elongation on solid support. Invaluable to monitor present strategy, a photocleavable linker allowed rapid, yet detailed analysis of side chain protected peptide intermediates, liberated from the sampled resin, by reverse-phase HPLC and MALDI-TOF-MS. By decorating each scaffold position with two basic region peptides in a 2 x 2 design, a first generation of unprecedented b(-HLH-) ZIP peptidosteroids was efficiently obtained. As such, a versatile methodology amenable to library generation is presented.
Keywords
Leucine zippers, ARTIFICIAL TRANSCRIPTION FACTORS, Protein models, Solid-phase synthesis, Peptidosteroids, Bioorganic chemistry, Peptides, DESORPTION/IONIZATION MASS-SPECTROMETRY, NITROBENZYL PHOTOLABILE LINKER, PROTEIN-DNA INTERACTIONS, REGION LEUCINE-ZIPPER, ZINC-FINGER PROTEINS, PEPTIDE-SYNTHESIS, BINDING-SPECIFICITY, ORGANIC-SYNTHESIS, DRUG DISCOVERY

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MLA
Verzele, Dieter, and Annemieke Madder. “Synthetic Progress in cMyc-Max Oncoprotein Miniaturization: Semi-online Monitoring Gives Solid-phase Access to Hydrophobic b(-HLH-)ZIP Peptidosteroid Tweezers.” EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 4 (2013): 673–687. Print.
APA
Verzele, D., & Madder, A. (2013). Synthetic progress in cMyc-Max oncoprotein miniaturization: semi-online monitoring gives solid-phase access to hydrophobic b(-HLH-)ZIP peptidosteroid tweezers. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, (4), 673–687.
Chicago author-date
Verzele, Dieter, and Annemieke Madder. 2013. “Synthetic Progress in cMyc-Max Oncoprotein Miniaturization: Semi-online Monitoring Gives Solid-phase Access to Hydrophobic b(-HLH-)ZIP Peptidosteroid Tweezers.” European Journal of Organic Chemistry (4): 673–687.
Chicago author-date (all authors)
Verzele, Dieter, and Annemieke Madder. 2013. “Synthetic Progress in cMyc-Max Oncoprotein Miniaturization: Semi-online Monitoring Gives Solid-phase Access to Hydrophobic b(-HLH-)ZIP Peptidosteroid Tweezers.” European Journal of Organic Chemistry (4): 673–687.
Vancouver
1.
Verzele D, Madder A. Synthetic progress in cMyc-Max oncoprotein miniaturization: semi-online monitoring gives solid-phase access to hydrophobic b(-HLH-)ZIP peptidosteroid tweezers. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY. 2013;(4):673–87.
IEEE
[1]
D. Verzele and A. Madder, “Synthetic progress in cMyc-Max oncoprotein miniaturization: semi-online monitoring gives solid-phase access to hydrophobic b(-HLH-)ZIP peptidosteroid tweezers,” EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, no. 4, pp. 673–687, 2013.
@article{4342528,
  abstract     = {Miniature versions of basic leucine zipper (bZIP) and basic helix-loop-helix zipper (b-HLH-ZIP) transcription factors are promising tools for molecular dissection of the genetic information in a post-genomic context. Despite the opportunities of genome interfering agents based on certain oncogenic zipper proteins, structural mimicry of transcription factors is a delicate undertaking, and experimental fine-tuning through bottom-up organic chemistry could benefit from solid-phase/library approaches. Involved in a variety of human pathologies, we became interested in the miniaturization of the cMyc-Max b-HLH-ZIP oncoprotein, and herein elaborate on our synthetic progress in that direction. A bile acid scaffold was successfully employed as artificial dimerization interface in this new type of transcription factor model. Orthogonality of the applied Alloc/Boc/Fmoc chemistries allowed the synthesis of both homo-and heterodimeric peptidosteroid conjugates, covalently restricted with defined geometrical properties. Recognition peptides were assembled through standard Fmoc/tBu solid-phase peptide synthesis (SPPS) chemistry, assisted by automated procedures for consecutive chain elongation on solid support. Invaluable to monitor present strategy, a photocleavable linker allowed rapid, yet detailed analysis of side chain protected peptide intermediates, liberated from the sampled resin, by reverse-phase HPLC and MALDI-TOF-MS. By decorating each scaffold position with two basic region peptides in a 2 x 2 design, a first generation of unprecedented b(-HLH-) ZIP peptidosteroids was efficiently obtained. As such, a versatile methodology amenable to library generation is presented.},
  author       = {Verzele, Dieter and Madder, Annemieke},
  issn         = {1434-193X},
  journal      = {EUROPEAN JOURNAL OF ORGANIC CHEMISTRY},
  keywords     = {Leucine zippers,ARTIFICIAL TRANSCRIPTION FACTORS,Protein models,Solid-phase synthesis,Peptidosteroids,Bioorganic chemistry,Peptides,DESORPTION/IONIZATION MASS-SPECTROMETRY,NITROBENZYL PHOTOLABILE LINKER,PROTEIN-DNA INTERACTIONS,REGION LEUCINE-ZIPPER,ZINC-FINGER PROTEINS,PEPTIDE-SYNTHESIS,BINDING-SPECIFICITY,ORGANIC-SYNTHESIS,DRUG DISCOVERY},
  language     = {eng},
  number       = {4},
  pages        = {673--687},
  title        = {Synthetic progress in cMyc-Max oncoprotein miniaturization: semi-online monitoring gives solid-phase access to hydrophobic b(-HLH-)ZIP peptidosteroid tweezers},
  url          = {http://dx.doi.org/10.1002/ejoc.201201235},
  year         = {2013},
}

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