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

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.

Resumen tomado de PubMed (NCBI) para el registro citado, en el idioma original. La versión de referencia es la de la publicación original.

El resumen se deja sin traducir para conservar la redacción original de los autores.

Inspired by hematophagous peptide inhibitors, bivalent EXACT inhibitors link thrombin or factor Xa exosite-binding aptamers to active-site small molecules; HD22-7A-DAB showed potent anticoagulant activity with potential to support cardiovascular surgery.

Explore cómo esta investigación se conecta con la práctica clínica

Más estudios revisados por pares en la categoría «Desarrollo de fármacos».

• Hirudoterapia en medicina y odontología — Jha K et al. (2015)
• Terapia con sanguijuelas: una historia — Hyson J (2005)
• Hirudinas de la sanguijuela medicinal asiática Hirudinaria manillensis: iguales, pero diferentes — Lukas P et al. (2019)
• Transcriptomic analysis of the salivary gland of medicinal leech Hirudo nipponia — Lu Z et al. (2018)
• Molecular dynamic and pharmacological studies on protein-engineered hirudin variants of Hirudinaria manillensis and Hirudo medicinalis — Sun Y et al. (2022)
• Síntesis acelular de la variante 1 de hirudina de la sanguijuela hematófaga Hirudo medicinalis — Wüstenhagen D et al. (2020)
• Producción de variantes de hirudina mediante fábricas microbianas modificadas genéticamente — Zhang J, Lan N (2018)
• Hirudina en la trombocitopenia inducida por heparina — Lubenow N, Greinacher A (2002)
• La hirudina mejora la nefropatía diabética al inhibir la piroptosis mediada por Gsdmd — Han J et al. (2023)
• La hirudina como anticoagulante alternativo: una revisión histórica — Markwardt F (2002)

Ver toda la investigación analizada por la ASH →