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.
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March 1993
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Research Article|
March 01 1993
Benzyloxycarbonyl-d-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position
G Claeson;
G Claeson
*Thrombosis Research Institute, Emmanuel Kaye Building, Manresa Road, London SW3 6LR, U.K.
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M Philipp;
M Philipp
†Lehman College and Graduate Center of The City University of New York, Bronx, NY 10468, U.S.A.
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E Agner;
E Agner
‡Kabi-Pharmacia AB, S-112 87 Stockholm, Sweden
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M F Scully;
M F Scully
*Thrombosis Research Institute, Emmanuel Kaye Building, Manresa Road, London SW3 6LR, U.K.
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R Metternich;
R Metternich
§Preclinical Research, Sandoz Pharma Ltd., CH-4002, Basel, Switzerland
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V V Kakkar;
V V Kakkar
*Thrombosis Research Institute, Emmanuel Kaye Building, Manresa Road, London SW3 6LR, U.K.
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T DeSoyza;
T DeSoyza
†Lehman College and Graduate Center of The City University of New York, Bronx, NY 10468, U.S.A.
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L H Niu
L H Niu
†Lehman College and Graduate Center of The City University of New York, Bronx, NY 10468, U.S.A.
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Publisher: Portland Press Ltd
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 1993 The Biochemical Society, London
1993
Biochem J (1993) 290 (2): 309–312.
Citation
G Claeson, M Philipp, E Agner, M F Scully, R Metternich, V V Kakkar, T DeSoyza, L H Niu; Benzyloxycarbonyl-d-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position. Biochem J 1 March 1993; 290 (2): 309–312. doi: https://doi.org/10.1042/bj2900309
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