BENZYLOXYCARBONYL-D-PHE-PRO-METHOXYPROPYLBOROGLYCINE - A NOVEL INHIBITOR OF THROMBIN WITH HIGH SELECTIVITY CONTAINING A NEUTRAL SIDE-CHAIN AT THE P1 POSITION

被引:29
作者
CLAESON, G
PHILIPP, M
AGNER, E
SCULLY, MF
METTERNICH, R
KAKKAR, VV
DESOYZA, T
NIU, LH
机构
[1] KABI PHARM AB,S-11287 STOCKHOLM,SWEDEN
[2] SANDOZ PHARMA LTD,PRECLIN RES,CH-4002 BASEL,SWITZERLAND
[3] CUNY HERBERT H LEHMAN COLL,BRONX,NY 10468
[4] CUNY,CTR GRAD,BRONX,NY 10468
关键词
D O I
10.1042/bj2900309
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 [K(i) (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.
引用
收藏
页码:309 / 312
页数:4
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