Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 67, Issue -, Pages 90-97Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.06.034
Keywords
Anticoagulants; Thrombin inhibition; DNA aptamers; G-Quadruplexes; Triazole internucleotide linkages
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Funding
- Russian Foundation for Basic Research [11-04-00131-a, 11-04-01544a, 11-04-02001a]
- Presidium of the Russian Academy of Sciences on Molecular and Cell Biology
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A series of DNA aptamers bearing triazole internucleotide linkages that bind to thrombin was synthesized. The novel aptamers are structurally analogous to the well-known thrombin-inhibiting G-quadruplexes TBA15 and TBA31. The secondary structure stability, binding affinity for thrombin and anticoagulant effects of the triazole-modified aptamers were measured. A modification in the central loop of the aptamer quadruplex resulted in increased nuclease resistance and an inhibition efficiency similar to that of TBA15. The likely aptamer-thrombin binding mode was determined by molecular dynamics simulations. Due to their relatively high activity and the increased resistance to nuclease digestion imparted by the triazole internucleotide linkages, the novel aptamers are a promising alternative to known DNA-based anticoagulant agents. (C) 2013 Elsevier Masson SAS. All rights reserved.
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