Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-κB

David E. Volk, Xianbin Yang, Susan M. Fennewald, David J. King, Suzanne E. Bassett, Sheela Venkitachalam, Norbert Herzog, Bruce A. Luxon, David G. Gorenstein

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A variety of monothio- and dithiosubstituted duplex aptamers targeting NF-κB have been synthesized and designed. The specificity and affinity of the dithioate aptamers of p50 and RelA(p65) NF-κB homodimers was determined by gel shift experiments. The NMR solution structures for several unmodified and dithioate backbone modified 14-base paired duplex aptamers have been determined by a hybrid, complete matrix (MORASS)/restrained molecular dynamics method. Structural perturbations of the dithioate substitutions support our hypothesis that the dithioate binds cations less tightly than phosphoryl groups. This increases the electrostatic repulsion across the B-form narrow minor groove and enlarges the minor groove, similar to that found in A-form duplexes. Structural analysis of modeled aptamer complexes with NF-κB homo- and heterodimers suggests that the dithioate backbone substitution can increase the aptamer's relative affinity to basic groups in proteins such as NF-κB by helping to "strip" the cations from the aptamer backbone.

Original languageEnglish
Pages (from-to)396-419
Number of pages24
JournalBioorganic Chemistry
Volume30
Issue number6
DOIs
StatePublished - Dec 2002

Fingerprint

Cations
Substitution reactions
Transcription Factors
Molecular Dynamics Simulation
Static Electricity
Structural analysis
Molecular dynamics
Electrostatics
Gels
Nuclear magnetic resonance
Proteins
Experiments

Keywords

  • Antisense
  • Dithioates
  • Monothioates
  • NF-κB
  • NMR
  • Solution structure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery

Cite this

Volk, D. E., Yang, X., Fennewald, S. M., King, D. J., Bassett, S. E., Venkitachalam, S., ... Gorenstein, D. G. (2002). Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-κB. Bioorganic Chemistry, 30(6), 396-419. https://doi.org/10.1016/S0045-2068(02)00510-2

Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-κB. / Volk, David E.; Yang, Xianbin; Fennewald, Susan M.; King, David J.; Bassett, Suzanne E.; Venkitachalam, Sheela; Herzog, Norbert; Luxon, Bruce A.; Gorenstein, David G.

In: Bioorganic Chemistry, Vol. 30, No. 6, 12.2002, p. 396-419.

Research output: Contribution to journalArticle

Volk, DE, Yang, X, Fennewald, SM, King, DJ, Bassett, SE, Venkitachalam, S, Herzog, N, Luxon, BA & Gorenstein, DG 2002, 'Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-κB', Bioorganic Chemistry, vol. 30, no. 6, pp. 396-419. https://doi.org/10.1016/S0045-2068(02)00510-2
Volk, David E. ; Yang, Xianbin ; Fennewald, Susan M. ; King, David J. ; Bassett, Suzanne E. ; Venkitachalam, Sheela ; Herzog, Norbert ; Luxon, Bruce A. ; Gorenstein, David G. / Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-κB. In: Bioorganic Chemistry. 2002 ; Vol. 30, No. 6. pp. 396-419.
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