Document Detail

Bivalent ligands with long nanometer-scale flexible linkers.
MedLine Citation:
PMID:  19113836     Owner:  NLM     Status:  MEDLINE    
High-affinity ligands recognizing biomolecules with high specificity are crucial for drug discovery and biomolecule detection. We describe here a simple approach to preparing aptamer-based ligands with enhanced binding affinity. In this approach, two aptamer ligands with suboptimal binding properties are covalently linked with a long flexible linker to create a bivalent ligand with significantly improved binding affinity. We first used a simple oligonucleotide-based model, which mimicked the interaction between bivalent ligands and their target molecules, to investigate the principles governing the affinity enhancement. These experiments showed that as long as the individual ligands had at least submicromolar binding affinities, they could be linked with a nanometer-scale flexible linker to produce bivalent ligands with improved binding affinity and specificity. Furthermore, comparison of the experimental data with the bivalent ligand properties predicted by a wormlike chain model showed that this model provided a good approximation of the binding properties of nanometer-scale flexible bivalent ligands. To verify the practicality of bivalent ligands with nanometer-scale flexible linkers, we constructed aptamer-based bivalent ligands for human alpha-thrombin. In agreement with the predictions derived from the model system, the binding affinities and the anticlotting activities of thrombin bivalent ligands were significantly improved compared to those of the individual ligands.
Ling Tian; Tomasz Heyduk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry     Volume:  48     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-14     Completed Date:  2009-02-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  264-75     Citation Subset:  IM    
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University Medical School, 1100 South Grand Boulevard, St. Louis, Missouri 63104, USA.
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MeSH Terms
Aptamers, Nucleotide / metabolism
Carbocyanines / metabolism
Fluorescence Polarization
Fluorescent Dyes / metabolism
Models, Molecular
Molecular Conformation
Molecular Structure
Nanotechnology / methods*
Oligonucleotides / metabolism
Partial Thromboplastin Time
SELEX Aptamer Technique
Thrombin / metabolism
Reg. No./Substance:
0/Aptamers, Nucleotide; 0/Carbocyanines; 0/Fluorescent Dyes; 0/Ligands; 0/Oligonucleotides; 0/cyanine dye 5; EC

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