Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic
Research article published in Protein science (1996)
Abstract
A new class of divalent thrombin inhibitors is described that contains an alpha-keto-amide transition-state mimetic linking an active site binding group and a group that binds to the fibrinogen-binding exosite. The X-ray crystallographic structure of the most potent member of this new class, CVS995, shows many features in common with other divalent thrombin inhibitors and clearly defines the transition-state-like binding of the alpha-keto-amide group. The structure of the active site part of the inhibitor shows a network of water molecules connecting both the side-chain and backbone atoms of thrombin and the inhibitor. Direct peptide analogues of the new transition-state-containing divalent thrombin inhibitors were compared using in vitro assays of thrombin inhibition. There was no direct correlation between the binding constants of the peptides and their alpha-keto-amide counterparts. The most potent alpha-keto-amide inhibitor, CVS995, with a Ki = 1 pM, did not correspond to the most potent divalent peptide and contained a single amino acid deletion in the exosite binding region with respect to the equivalent region of the natural thrombin inhibitor hirudin. The interaction energies of the active site, transition state, and exosite binding regions of these new divalent thrombin inhibitors are not additive.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic.
Por qué esto importa para la hirudoterapia
El resumen describe una nueva clase de inhibidores divalentes de la trombina que contienen un mimético del estado de transición de alfa-ceto-amida, informando la estructura cristalográfica de rayos X del miembro más potente (CVS995, Ki = 1 pM) y comparando análogos peptídicos directos en ensayos in vitro de inhibición de la trombina. La hirudina se menciona solo como un «inhibidor natural de la trombina» cuya región de unión al exosito difiere por una sola deleción de aminoácido en el inhibidor más potente. La conexión con las sanguijuelas o la hirudoterapia es en el mejor de los casos indirecta: el resumen no menciona sanguijuelas, secreciones de sanguijuelas ni hirudoterapia, y todos los compuestos descritos son miméticos químicos sintéticos en lugar de productos naturales derivados de sanguijuelas.
Citación
Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic
Krishnan R et al. · Protein science, 1996
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026