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.
Resumen
Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.
Por qué esto importa para la hirudoterapia
Este estudio diseña «inhibidores EXACT» mediante la unión de aptámeros de unión a exositio a inhibidores de sitio activo de molécula pequeña, dirigidos a la trombina y al factor Xa. El componente aptamérico sinergiza con los inhibidores de sitio activo (potenciando la potencia varios cientos de veces), puede redirigir la selectividad hacia una proteasa diferente y permite la reversión mediante un antídoto. Un inhibidor, HD22-7A-DAB, demuestra una potente actividad anticoagulante con potencial para cirugías cardiovasculares. El diseño está inspirado en organismos hematófagos que combinan la unión a exositio y a sitio activo en inhibidores peptídicos. La relevancia para ASH es limitada: el resumen no menciona específicamente sanguijuelas, hirudina ni moléculas derivadas de sanguijuela, y el estudio utiliza constructos diseñados sintéticamente en lugar de productos naturales de sanguijuela. Advertencia: el resumen no especifica el contexto experimental, y no se establece una conexión directa con la hirudoterapia.
Citación
Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors
Yu HC et al. · Nature communications, 2024
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026