American Society of Hirudotherapy

Hirulog peptides with scissile bond replacements resistant to thrombin cleavage

Research article published in Biochemical and biophysical research communications (1991)

Last Updated: June 18, 2026Reviewed by: ASH Editorial Board
Research article — evidence reviewArticle reference
Evidence: Research reportDrug DevelopmentKline T et al. · Biochemical and biophysical research communications, 1991

Abstract

Using the natural protein hirudin as a model, a novel class of synthetic peptide inhibitors were recently designed. These inhibitors, 'hirulogs', retain the carboxy terminal Hir53-64 domain that interacts with the anion binding exosite of thrombin, connected via an oligoglycyl spacer unit to a catalytic site-directed moiety modeled on the sequence [D]Phe-Pro-Arg-X. The scissile Arg-X bond bond of substrate-like inhibitors has been modified to the proteolytic-resistant functions as beta-homo amino acids Arg psi [CH2CONH] X (2) and reduced bond analogues Arg psi [CH2N]X (3). Both classes of compounds demonstrate inhibition of thrombin amidolytic activity, and this active-site inhibition is highly sensitive to the P1' residue X. Thus these hirulog derivatives are resistant to thrombin proteolysis while maintaining substrate-like interactions with the active center. Finally, hirulog derivatives with non-cleavable replacements of the scissile bond are found to be effective anticoagulant agents.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Publication typeJournal Article
Indexed MeSH termsAmino Acid SequenceHirudinsHumansIndicators and ReagentsKineticsMolecular Sequence DataOligopeptidesStructure-Activity RelationshipThrombin

Summary

Hirulog peptides with scissile bond replacements resistant to thrombin cleavage.

Why This Matters for Hirudotherapy

This research investigated 'hirulogs,' a novel class of synthetic peptide inhibitors modeled on natural leech hirudin, focusing on modifications to the scissile bond that make them resistant to thrombin cleavage while maintaining anticoagulant activity. This is relevant to the ASH domain because it directly translates the structural mechanism of a key leech secretome component (hirudin) into viable pharmacological design principles for new anticoagulant agents. The findings reinforce the therapeutic robustness of hirudin's dual-binding mechanism. However, an essential caveat is that this study focuses purely on chemically synthesized mimetics of leech peptides; it involves no actual leeches, natural secretions, or whole-organism hirudotherapy.

Citation

Hirulog peptides with scissile bond replacements resistant to thrombin cleavage

Kline T et al. · Biochemical and biophysical research communications, 1991

DOI

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