Benzyloxycarbonyl-D-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position.
Thrombin, the blood-clotting enzyme, is a serine proteinase with trypsin-like specificity and is able to cleave Arg-Xaa peptide bonds but only in a very limited number of substrates (and sites therein). For the prevention and treatment of thrombosis the control of thrombin activity is a key target, and a variety of synthetic inhibitors have been introduced recently, all of which have a positive charge at the P1 site. We report the synthesis of the first example of a new class of inhibitor containing a neutral side chain at the P1 site, the peptide benzyloxycarbonyl-D-Phe-Pro- methoxypropylboroglycine. The peptide is a potent inhibitor of thrombin [Ki (limiting) = 7 nM] and is highly selective for its target enzyme in respect of other serine proteinases. This may be expected to confer considerable advantage in terms of specificity of action and reduced toxicity over conventional, positively charged, inhibitors.
Claeson
G
G
Thrombosis Research Institute, London, U.K.
Philipp
M
M
Agner
E
E
Scully
M F
MF
Metternich
R
R
Kakkar
V V
VV
DeSoyza
T
T
Niu
L H
LH
D000595:Amino Acid Sequence; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D010959:Tissue Plasminogen Activator / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology
D001643:Bridged Bicyclo Compounds; D009842:Oligopeptides; C080019:benzyloxycarbonyl-phenylalanyl-prolyl-methoxypropylglycine-pinanediol; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator