Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors
Research article published in Nature communications (2024)
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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Zusammenfassung
Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.
Warum dies für die Hirudotherapie relevant ist
This study engineers 'EXACT inhibitors' by linking exosite-binding aptamers to small-molecule active-site inhibitors, targeting thrombin and factor Xa. The aptamer component synergizes with active-site inhibitors (enhancing potency many hundred-fold), can redirect selectivity toward a different protease, and enables reversal by an antidote. One inhibitor, HD22-7A-DAB, demonstrates potent anticoagulation activity with potential for cardiovascular surgeries. The design is inspired by hematophagous organisms that combine exosite and active-site binding in peptide inhibitors. Relevance to ASH is limited: the abstract does not specifically mention leeches, hirudin, or leech-derived molecules, and the study uses synthetically engineered constructs rather than natural leech products. Caveat: the abstract does not specify experimental context, and no direct connection to hirudotherapy is established.
Zitation
Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors
Yu HC et al. · Nature communications, 2024
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