Crystal structure of thrombin in complex with S-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors
Research article published in PloS one (2011)
Abstract
The inhibition of thrombin is one of the important treatments of pathological blood clot formation. Variegin, isolated from the tropical bont tick, is a novel molecule exhibiting a unique 'two-modes' inhibitory property on thrombin active site (competitive before cleavage, noncompetitive after cleavage). For the better understanding of its function, we have determined the crystal structure of the human α-thrombin:synthetic-variegin complex at 2.4 Å resolution. The structure reveals a new mechanism of thrombin inhibition by disrupting the charge relay system. Based on the structure, we have designed 17 variegin variants, differing in potency, kinetics and mechanism of inhibition. The most active variant is about 70 times more potent than the FDA-approved peptidic thrombin inhibitor, hirulog-1/bivalirudin. In vivo antithrombotic effects of the variegin variants correlate well with their in vitro affinities for thrombin. Our results encourage that variegin and the variants show strong potential for the development of tunable anticoagulants.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
The inhibition of thrombin is one of the important treatments of pathological blood clot formation.
Por qué esto importa para la hirudoterapia
Este artículo describe la estructura cristalina a 2.4 Å de la alfa-trombina humana complejada con variegin sintética, un inhibidor de trombina aislado de la garrapata tropical bont, e informa el diseño de 17 variantes de variegin. El resumen señala que la variante más activa es aproximadamente 70 veces más potente que el inhibidor peptídico de trombina aprobado por la FDA, hirulog-1/bivalirudin, y que los efectos antitrombóticos in vivo de las variantes se correlacionan con sus afinidades in vitro por la trombina. Para ASH, la relevancia es indirecta: hirulog-1/bivalirudin se emplea como comparador de referencia, aunque el resumen lo describe únicamente como un inhibidor peptídico de trombina aprobado por la FDA sin caracterizar su relación con la hirudina. La salvedad es que variegin proviene de garrapatas, no de sanguijuelas, y el estudio no involucra directamente a la hirudoterapia ni al secretoma de la sanguijuela.
Citación
Crystal structure of thrombin in complex with S-variegin: insights of a novel mechanism of inhibition and design of tunable thrombin inhibitors
Koh CY et al. · PloS one, 2011
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026