title: Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan.
abstract: 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.
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Longyan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China;
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Chuang
authors.initials: C
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China;
authors.forename: Lian
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Lutan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Na
authors.initials: N
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China;
authors.forename: Zi
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China;
authors.forename: Jianchao
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China jkliu@mail.kib.ac.cn qinhongbo@mail.kib.ac.cn zhaojinhua@mail.kib.ac.cn.
authors.forename: Jikai
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; jkliu@mail.kib.ac.cn qinhongbo@mail.kib.ac.cn zhaojinhua@mail.kib.ac.cn.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; jkliu@mail.kib.ac.cn qinhongbo@mail.kib.ac.cn zhaojinhua@mail.kib.ac.cn.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D002240:Carbohydrate Sequence; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005643:Fucose / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D020246:Venous Thrombosis / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D004791:Enzyme Inhibitors; D006025:Glycosaminoglycans; D009363:Neoplasm Proteins; D009844:Oligosaccharides; D005643:Fucose; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant
keywords: anticoagulant; carbohydrates; drug discovery; inhibitors; oligosaccharides