Synergistic effect of aptamers that inhibit exosites 1 and 2 on thrombin.

Journal Article (Journal Article)

Thrombin is a multifunctional protease that plays a key role in hemostasis, thrombosis, and inflammation. Most thrombin inhibitors currently used as antithrombotic agents target thrombin's active site and inhibit all of its myriad of activities. Exosites 1 and 2 are distinct regions on the surface of thrombin that provide specificity to its proteolytic activity by mediating binding to substrates, receptors, and cofactors. Exosite 1 mediates binding and cleavage of fibrinogen, proteolytically activated receptors, and some coagulation factors, while exosite 2 mediates binding to heparin and to platelet receptor GPIb-IX-V. The crystal structures of two nucleic acid ligands bound to thrombin have been solved. Previously Padmanabhan and colleagues solved the structure of a DNA aptamer bound to exosite 1 and we reported the structure of an RNA aptamer bound to exosite 2 on thrombin. Based upon these structural studies we speculated that the two aptamers would not compete for binding to thrombin. We observe that simultaneously blocking both exosites with the aptamers leads to synergistic inhibition of thrombin-dependent platelet activation and procoagulant activity. This combination of exosite 1 and exosite 2 inhibitors may provide a particularly effective antithrombotic approach.

Full Text

Duke Authors

Cited Authors

  • Nimjee, SM; Oney, S; Volovyk, Z; Bompiani, KM; Long, SB; Hoffman, M; Sullenger, BA

Published Date

  • December 2009

Published In

Volume / Issue

  • 15 / 12

Start / End Page

  • 2105 - 2111

PubMed ID

  • 19846574

Pubmed Central ID

  • PMC2779679

Electronic International Standard Serial Number (EISSN)

  • 1469-9001

Digital Object Identifier (DOI)

  • 10.1261/rna.1240109


  • eng

Conference Location

  • United States