Hirulog peptides with scissile bond replacements resistant to thrombin cleavage

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.

Hirulog inhibitors with the scissile Arg-X bond replaced by beta-homo amino acid or reduced-bond linkages resisted thrombin proteolysis while preserving substrate-like active-site binding (highly sensitive to the P1' residue) and remained effective anticoagulants.

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