John M. Maraganore

Bedeutung für die Hirudotherapie

John M. Maraganore's research at Biogen Inc. in Cambridge, Massachusetts, centred on hirudin and its conversion into synthetic antithrombotic agents. In 1989 he and colleagues synthesised peptides based on the carboxy-terminal 21 residues of hirudin, mapped the minimal twelve-residue sequence retaining maximal anticoagulant activity, and showed that tyrosine sulfation enhanced inhibitory potency by roughly an order of magnitude (PMID 2722794). In 1990 the same group designed the hirulogs, bivalent peptides uniting an active-site sequence with a hirudin-derived anion-binding-exosite recognition element through a glycyl linker; Hirulog-1 inhibited thrombin with a Ki of 2.3 nM (PMID 2223763). Hirulog — indexed by PubMed under the substance name bivalirudin — was subsequently studied for prevention of deep-vein thrombosis, unstable angina, acute myocardial infarction during thrombolysis and complications of PTCA, as Maraganore reviewed in 1996 (PMID 8889359). He later co-authored analyses showing that heparin anticoagulation varies widely and can be blunted in plasma from patients with acute coronary syndromes, whereas bivalirudin responses are more predictable (PMID 17221324). The large clinical trials of bivalirudin were run by others: in the 2008 HORIZONS-AMI trial of 3,602 patients with ST-elevation myocardial infarction undergoing primary PCI, Stone and colleagues reported that bivalirudin alone, compared with heparin plus a glycoprotein IIb/IIIa inhibitor, reduced 30-day net adverse clinical events (9.2% vs 12.1%) and major bleeding (4.9% vs 8.3%) (PMID 18499566). Maraganore later became chief executive of Alnylam Pharmaceuticals.