Hirulog

Bivalent inhibitors of thrombin have been synthesized to bind the anion-binding exosite and active (catalytic) site of thrombin simultaneously. By coupling the carboxy terminal fragment of hirudin to a tripeptide (D-Phe-Pro-Arg) by including a spacer molecule, both the anion exosite and the catalytic site are blocked. An example of such a molecule is Hirulog, which has 20 amino acids and has a Kj of 2 nM (61). Its ability to block the active site has been questioned, since thrombin has been shown to cleave the Arg-Pro bond of Hirulog slowly in vivo (58). In addition to hirudin and hirudin-like compounds, three other classes of site-directed thrombin inhibitors deserve mention. 

Direct thrombin inhibitors such as hirudin, Hirulog, the peptide aldehyde efegatran, and peptidomimetic compound argatroban have undergone clinical trials. Their application in the prevention and treatment of deep vein thrombosis contin-... 

Maraganore J. M., Bourdon P Jablonskj J., Ramachandran K. L. Design and characterization of hirulogs A novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990 229, 7095-101. 

Witting JI, Bourdon P, Maraganore JM, Fenton JW II. Hirulog-1 and -B2 thrombin specificity. Biochem J 1992 287 663-664. 

Bourdon P, Jablonski J, Chao BH, Maraganore JM. Structure-function relationships of hirulog peptide interactions with thrombin. FEBS 1991 294 163-166. 

Parry MA, Maraganore JM, Stone SR, Kinetic mechanism for the interaction of hirulog with thrombin, Biochemistry 1994 33 14807-14814. 

Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995 333 764-769. 

The Hirulog Early Reperfusion or Occlusion (HERO) trial was conducted in patients with AMI to investigate the effects of bivalirudin in combination with SKand aspirin (Table 5) (66). Four hundred and twelve patients who presented with onset of ST elevation within 12 hours were randomized in a double-blind manner to one of three adjunctive anticoagulation regimens, UFH, low-dose or high-dose bivalirudin. The... 

Abbreviations AMI, acute myocardial infarction HERO, hirulog early reperfusion or occlusion SK, streptokinase TIMI, thrombolysis in myocardial infarction UFH, unfractionated heparin. 

Topol EJ, Bonan R, Jewitt D, et al, Use of a direct antithrombin, Hirulog, in place of heparin during coronary angioplasty, Circulation 1993 87 1622-1629,... 

White HD, Aylward PE, Frey MJ, et al. Randomized, doubleblind comparison of Hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation I 997 96 21 55-2161. 

The Hirulog and Early Reperfusion or Occlusion (HERO) -2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction the HERO-2 randomised trial. Lancet 2001 3 58 1 855-1 863,... 

The active substance in bivalirudin (Hirulog), a direct thrombin inhibitor, is a 20-amino acids ynthetic peptide based on the hirudin template. In the Hirulog angioplasty study, 4098 patients with unstable or post infarction angina were randomized to bivalirudin or heparin before PTCA (14). The conclusion of this study was that there was no difference in the 30-day primary endpoint with either treatment. Patients randomized to Hirulog, however, did have a statistically significant reduced incidence of bleeding-related complications. 

A 20 amino acid polypeptide [1], bivalirudin (hirulog) is a synthetic version of hirudin. Its amino-terminal D-Phe-Pro-Arg-Pro domain, which interacts with the active site of thrombin, is linked via four Gly residues to a dodecapeptide analogue of the carboxy-terminal of hirudin. Like hirudin, bivalirudin also forms a 1 1 stoichiometric complex with thrombin. Once bound, however, the Arg-Pro bond at the amino-terminal of bivalirudin is cleaved by thrombin, thereby restoring active site functions of the enzyme complexes of a-thrombin [2]. 

Hirulog-8 has the formula H-(D-Phe)-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH. Hirulog-8 was synthesized by conventional solid-phase peptide synthesis employing an Applied Biosystems 430 A Peptide Synthesizer. This peptide was synthesized using BOC-L-Leucine-O-divinylbenzene resin. Additional t-BOC-amino acids (Peninsula Laboratories,... 

The structure of purified Hirulog-8 was confirmed by amino acid and sequence analyses. 

Yenari MA, de Crespigny A, Palmer JT, Roberts S, Schrier SL, Albers GW, Moseley ME, Steinberg GK (1997) Improved perfusion with rt-PA and hirulog in a rabbit model of embolic stroke. J Cereb Blood Flow Metab 17 401-411... 

Hirulogs Synthetic bifunctional Several clinical studies are... 

Wong CK, Gao W, Stewart RA et al. Hirulog Early Reperfusion Occlusion (HERO-2) Investigators. Risk stratification of patients with acute anterior myocardial infarction and right bundle-branch block importance of QRS duration and early ST-segment resolution after fibrinolytic therapy. Circulation 2006b 114(8) 783. 

In view of the overwhelming evidence implicating thrombin as the primary mediator of arterial thrombosis (vide supra), numerous thrombin inhibitors have been evaluated in various experimental models of thrombosis [73,74] while hirudin and Hirulog have progressed to advanced stages of clinical development [75]. 

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