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

Abstract

A variety of monothio- and dithiosubstituted duplex aptamers targeting NF-kappaB have been synthesized and designed. The specificity and affinity of the dithioate aptamers of p50 and RelA(p65) NF-kappaB 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-kappaB homo- and heterodimers suggests that the dithioate backbone substitution can increase the aptamer's relative affinity to basic groups in proteins such as NF-kappaB by helping to "strip" the cations from the aptamer backbone.

Cite this paper

@article{Volk2002SolutionSA, title={Solution structure and design of dithiophosphate backbone aptamers targeting transcription factor NF-kappaB.}, author={David E. Volk and Xianbin Yang and Susan M. Fennewald and David J. King and Suzanne E Bassett and Sheela Venkitachalam and Norbert K. Herzog and Bruce A. Luxon and David G . Gorenstein}, journal={Bioorganic chemistry}, year={2002}, volume={30 6}, pages={396-419} }