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Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors

Author

Listed:
  • Haixiang Yu

    (Duke University)

  • Shekhar Kumar

    (Children’s Hospital of Philadelphia)

  • James W. Frederiksen

    (Duke University)

  • Vladimir N. Kolyadko

    (Children’s Hospital of Philadelphia)

  • George Pitoc

    (Duke University)

  • Juliana Layzer

    (Duke University)

  • Amy Yan

    (Duke University)

  • Rachel Rempel

    (Duke University)

  • Samuel Francis

    (Duke University Hospital)

  • Sriram Krishnaswamy

    (Children’s Hospital of Philadelphia)

  • Bruce A. Sullenger

    (Duke University
    Duke University)

Abstract

Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor’s selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.

Suggested Citation

  • Haixiang Yu & Shekhar Kumar & James W. Frederiksen & Vladimir N. Kolyadko & George Pitoc & Juliana Layzer & Amy Yan & Rachel Rempel & Samuel Francis & Sriram Krishnaswamy & Bruce A. Sullenger, 2024. "Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48211-6
    DOI: 10.1038/s41467-024-48211-6
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    References listed on IDEAS

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    1. Christopher P. Rusconi & Elizabeth Scardino & Juliana Layzer & George A. Pitoc & Thomas L. Ortel & Dougald Monroe & Bruce A. Sullenger, 2002. "RNA aptamers as reversible antagonists of coagulation factor IXa," Nature, Nature, vol. 419(6902), pages 90-94, September.
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