N-terminal requirements of small peptide anticoagulants based on hirudin54-65
Research article published in Journal of medicinal chemistry (1988)
Abstract
C-terminal fragment analogues of the leech anticoagulant peptide hirudin represent a unique class of thrombin inhibitors that blocks thrombin's cleavage of fibrinogen but does not block the catalytic site of thrombin. In this paper, a series of synthetic peptides were prepared by solid-phase methodology to determine the optimal N-terminal and position 56 functionalities for these C-terminal fragment analogues of hirudin. Inhibition of fibrin clot formation by thrombin in vitro was used as a measure of anticoagulant activity. In the minimal C-terminal sequence necessary for anticoagulant activity, hirudin56-64, an L aromatic amino acid is required at position 56. Phe56----Tyr substitution retained potency, whereas p-Cl-Phe56 and phenylglycine56 substitutions resulted in decreased potencies. Removal of the cationic amino functionality from the vicinity of Asp55 results in increased potency (e.g., hirudin54-65, Ac-hirudin55-65) and [desNH2-Asp55]hirudin55-65 has a marked increase in potency over hirudin55-65. [DesNH2-Phe56]hirudin56-65 and related analogues show no detectable anticoagulant activity. The sensitivity of position 56 to modification demonstrates the significance of this residue in the interaction between the C-terminal region of hirudin and thrombin.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
C-terminal fragment analogues of the leech anticoagulant peptide hirudin represent a unique class of thrombin inhibitors that blocks thrombin's cleavage of fibrinogen but does not block the catalytic site of thrombin.
Por qué esto importa para la hirudoterapia
This study synthesized a series of C-terminal fragment analogues of hirudin (residues 54–65 and truncated variants) by solid-phase peptide methodology and evaluated their anticoagulant activity via in vitro inhibition of thrombin-mediated fibrin clot formation. Key findings included that an L-aromatic amino acid is required at position 56 for activity, that removing the cationic amino functionality near Asp55 increases potency, and that position 56 is highly sensitive to modification—demonstrating its critical role in the hirudin–thrombin interaction. This article is directly and centrally relevant to ASH's domain: it concerns the structure-activity relationships of hirudin, the signature anticoagulant peptide of the medicinal leech, and characterizes the minimal sequence requirements for its anticoagulant function. The main caveat is that this is purely in vitro biochemical/pharmacological research using synthetic peptides, not a study of living leeches, leech therapy, or the complete leech secretome.
Citación
N-terminal requirements of small peptide anticoagulants based on hirudin54-65
Owen TJ et al. · Journal of medicinal chemistry, 1988
Contexto clínico relacionado
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: June 18, 2026