Potent anticoagulant aptamer directed against factor IXa blocks macromolecular substrate interaction.

Published

Journal Article

An aptamer targeting factor IXa has been evaluated in animal models and several clinical studies as a potential antithombotic therapy. We elucidate the molecular mechanism by which this aptamer acts as an anticoagulant. The aptamer binds tightly to factor IXa and prolongs the clotting time of human plasma. The aptamer completely blocks factor IXa activation of factor X regardless of the presence of factor VIIIa. However, the aptamer does not completely block small synthetic substrate cleavage, although it does slow the rate of cleavage. These data are consistent with the aptamer binding to the catalytic domain of factor IXa in such a way as to block an extended substrate-binding site. Therefore, unlike small molecule inhibitors, aptamers appear to be able to bind surfaces surrounding an active site and thereby sterically interfere with enzyme activity. Thus, aptamers may be useful agents to probe and block substrate-binding sites outside of the active site of an enzyme.

Full Text

Duke Authors

Cited Authors

  • Sullenger, B; Woodruff, R; Monroe, DM

Published Date

  • April 13, 2012

Published In

Volume / Issue

  • 287 / 16

Start / End Page

  • 12779 - 12786

PubMed ID

  • 22334679

Pubmed Central ID

  • 22334679

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.M111.300772

Language

  • eng

Conference Location

  • United States