Development of MDL 28,050, a small stable antithrombin agent based on a functional domain of the leech protein, hirudin.

  title={Development of MDL 28,050, a small stable antithrombin agent based on a functional domain of the leech protein, hirudin.},
  author={John L Krstenansky and Robert J. Broersma and Thomas J. Owen and Marguerite H. Payne and Mark T. Yates and Simon J. T. Mao},
  journal={Thrombosis and haemostasis},
  volume={63 2},
MDL 28,050 is a decapeptide antithrombin agent that inhibits alpha-thrombin-induced fibrin clot formation by binding to a non-catalytic site on alpha-thrombin. It is the result of chemical and structural optimization of a functional domain of the leech anticoagulant, hirudin. In contrast to the contention that the polyanionic nature of this C-terminal functional domain governs its interaction with alpha-thrombin, systematic study of this region has shown the importance of the lipophilic… 
Interactions of hirudin-based inhibitor with thrombin: critical role of the IleH59 side chain of the inhibitor.
Theoretical free energy calculation successfully reproduces the binding free energy of most of the analogs and suggests that intra- and intermolecular van der Waals interactions of delta-CH3, gamma- CH3, and gamma-CH2 of IleH59 play the major role in the binding affinity.
Thrombin inhibitors A new generation of antithrombotics.
  • S. Stone
  • Medicine
    Trends in cardiovascular medicine
  • 1995
Conformationally restricted thrombin inhibitors resistant to proteolytic digestion.
A new type of thrombin exo-site inhibitor has been designed with enhanced inhibitory potency and increased metabolic stability and remarkable enhancement of stability to proteolysis was observed for peptide bonds located in the exocyclic linear peptide segments.
Systematic study of the substituted active C-terminus of hirudin.
This paper systematically synthesizes a series of C-terminal (desulfo hirudin45-65) peptides substituted by 20 natural L-amino acids via the Multipin method, and screens the resulting peptide library using an alpha-thrombin-mediated fibrinogen clotting assay and amidolytic hydrolysis assay.
Conformational stability of a thrombin-binding peptide derived from the hirudin C-terminus.
The thrombin-bound structure of the peptide fragment, hirudin 55-65, has been determined by use of transferred NOE spectroscopy and the apparent preference for a gauche- (chi 1 = +60) side-chain conformation of Ile(59) in the bound state may be explained by the existence of a positively charged arginine residue among the hydrophobic residues in theThrombin exosite.
Design of potent bivalent thrombin inhibitors based on hirudin sequence: incorporation of nonsubstrate-type active site inhibitors.
The crystal structure of the inhibitor in complex with human alpha-thrombin showed that dansyl, Arg, and D-pipecolic acid of the active site blocking moiety occupy S3, S2, and S2 subsites of thrombin, respectively, and were therefore designated as P3, P1, and P2 residues.
Hirunorms are true hirudin mimetics. The crystal structure of human α‐thrombin‐hirunorm V complex
The crystal structure of the complex formed by human α‐thrombin and hirunorm V, a 26‐residue polypeptide containing non‐natural amino acids, is determined at 2.1 Å resolution and it reveals that the inhibitor binding mode is distinctive of a true hirudin mimetic.