期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：27
页码：8284-8289
DOI：10.1073/pnas.1504229112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSelective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants without serious bleeding consequences. We prepared and identified a series of oligosaccharides as inhibitors of the intrinsic tenase, which is the final and rate-limiting enzyme complex in the intrinsic coagulation pathway and is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Analysis of these purified oligosaccharides reveals the precise structure of fucosylated glycosaminoglycan. Among these oligosaccharides, nonasaccharide is the minimum fragment that retains potent anticoagulant activity by selective inhibition of the intrinsic tenase while avoiding adverse effects and, thus, it may pave the way for the development of better treatments for thromboembolic diseases. Selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants that do not cause serious bleeding. Intrinsic tenase, the final and rate-limiting enzyme complex in the intrinsic coagulation pathway, is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Fucosylated glycosaminoglycan (FG), which has a distinct but complicated and ill-defined structure, is a potent natural anticoagulant with nonselective and adverse activities. Herein we present a range of oligosaccharides prepared via the deacetylation-deaminative cleavage of FG. Analysis of these purified oligosaccharides reveals the precise structure of FG. Among these fragments, nonasaccharide is the minimum fragment that retains the potent selective inhibition of the intrinsic tenase while avoiding the adverse effects of native FG. In vivo, the nonasaccharide shows 97% inhibition of venous thrombus at a dose of 10 mg/kg in rats and has no obvious bleeding risk. This nonasaccharide may therefore serve as a novel promising anticoagulant.
关键词：anticoagulant ; inhibitors ; oligosaccharides ; carbohydrates ; drug discovery
