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

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

• Book ID: 104266480
• Publisher: Elsevier Science
• Year: 2002
• Tongue: English
• Weight: 567 KB
• Volume: 30
• Category: Article
• ISSN: 0045-2068
• DOI: 10.1016/s0045-2068(02)00510-2

✦ Synopsis

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.