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Nucleic Acids Res. 2016 Sep 30;44(17):8052-64. doi: 10.1093/nar/gkw725. Epub 2016 Aug 26.

Evoking picomolar binding in RNA by a single phosphorodithioate linkage.

Author information

1
AM Biotechnologies, LLC, 12521 Gulf Freeway, Houston, TX 77034, USA.
2
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA martin.egli@vanderbilt.edu.
3
Department of Biology, Texas A&M University, College Station, TX 77843, USA.
4
Biointeractions Division, Horiba Scientific, Avenue de la Vauve - Passage JobinYvon CS 45002 Palaiseau, France.
5
Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941, Brazil.
6
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
7
Instituto de Bioquimica Médica Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941, Brazil.
8
Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Lodz, Sienkiewicza 112, Poland.
9
MilliporeSigma, 9186 Six Pines, The Woodlands, TX 77380, USA.
10
The Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.
11
School of Pharmaceutical Sciences, Zhengzhou University, Science Avenue 100, Zhengzhou 450001, Henan, China.
12
Departments of Gynecologic Oncology and Cancer Biology, and Center for RNAi and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
13
Departments of Chemistry and Pharmacology, and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA.
14
AM Biotechnologies, LLC, 12521 Gulf Freeway, Houston, TX 77034, USA Xianbin.yang@thioaptamer.com xianbin@hotmail.com.

Abstract

RNA aptamers are synthetic oligonucleotide-based affinity molecules that utilize unique three-dimensional structures for their affinity and specificity to a target such as a protein. They hold the promise of numerous advantages over biologically produced antibodies; however, the binding affinity and specificity of RNA aptamers are often insufficient for successful implementation in diagnostic assays or as therapeutic agents. Strong binding affinity is important to improve the downstream applications. We report here the use of the phosphorodithioate (PS2) substitution on a single nucleotide of RNA aptamers to dramatically improve target binding affinity by ∼1000-fold (from nanomolar to picomolar). An X-ray co-crystal structure of the α-thrombin:PS2-aptamer complex reveals a localized induced-fit rearrangement of the PS2-containing nucleotide which leads to enhanced target interaction. High-level quantum mechanical calculations for model systems that mimic the PS2 moiety and phenylalanine demonstrate that an edge-on interaction between sulfur and the aromatic ring is quite favorable, and also confirm that the sulfur analogs are much more polarizable than the corresponding phosphates. This favorable interaction involving the sulfur atom is likely even more significant in the full aptamer-protein complexes than in the model systems.

PMID:
27566147
PMCID:
PMC5041495
DOI:
10.1093/nar/gkw725
[Indexed for MEDLINE]
Free PMC Article

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