Research by a team from the Kunming Institute of Botany (KIB) of Chinese Academy of Sciences has identified a compound with potential as a novel anticoagulant due to its negligible bleeding risk.

The discovery is significant since thrombotic disease – as one of the major causes of human death – is often treated with anticoagulants. However, almost all anticoagulants currently in use entail a severe risk of bleeding. Because intrinsic coagulant factors are necessary for thrombosis but not required for hemostasis, developing new anticoagulants that selectively inhibit intrinsic coagulant factors has thus become a hot and challenging focus in the field.

Theoretically, intrinsic tenase is the final and rate-limiting enzyme complex in the intrinsic pathway of the blood coagulation cascade. It is an attractive but less explored target for developing new anticoagulants due to the lack of pure selective inhibitors. Interestingly, a series of oligosaccharides with potent and selective inhibition for intrinsic tenase were first purified by Prof. ZHAO Jinhua’s group from KIB (Proc. Natl. Acad. Sci. USA). The purified oligosaccharides particularly inhibit the intrinsic pathway, while having little effect on the extrinsic and common pathways of the blood coagulation cascade, highlighting the potential for the development of compound(s) for treatment of thrombotic disease.

In this research, compound 5 is the smallest compound among those oligosaccharides having strong anti-tenase activity. Using a rat venous thrombosis model, the researchers showed that the compound demonstrates significant antithrombotic activity – as strong as the most commonly used clinical drug, Enoxaparin. Importantly, the compound has no significant effect on hemostatic function even at a high dose, whereas Enoxaparin is associated with significant hemorrhagic tendency. This result demonstrates the potential for development of a better drug in the near future. In addition, the finding is very useful for clarifying the difference between physiological hemostasis and pathological thrombosis.

The oligosaccharides were obtained from fucosylated glycosaminoglycan (FG), which is a natural product extracted from sea cucumber. However, the precise structure of native FG was not elucidated for many years due to the difficulty of conducting chemical research on complicated polysaccharides. Additionally, FG has nonselective intrinsic tenase inhibitory activity, but its application is limited to its activation of F.XII and platelets. Since 2010, Prof. ZHAO’s group has been devoted to investigating the chemical structure of FG and the structure-function relationship of the inhibition of tenase, and has made progress in depolymerization of FG by selective glucosidic bond cleavage (Gao N, Lu F et al. Carbohydr Polym, 2015, 127, 427–437; Zhao LY, Lai SS et al. Carbohydr Polym, 2013, 98, 1514–1523), chemical modification (Gao N, Wu MY et al. Mar Drugs, 2012, 10, 1647–1661; Lian W, Wu MY et al. Biochim Biophys Acta, 2013, 1830, 4681–4691) and the structure-function relationships of FG (Wu MY, Wen DD et al. Eur J Med Chem, 2015, 92, 257–269). Now, ZHAO Longyan and WU Mingyi et al. are the first to report a series of oligosaccharides compounds prepared from FG by selective glucosidic bond clevage and purification techniques, and have elucidated the precise chemical structure of complicated FG through the structural analysis of purified oligosaccharide compounds.

Supporting information is available at: http://www.pnas.org/content/early/2015/06/17/1504229112.full.pdf 

This work was funded in part by the Yunnan Provincial Science and Technology Department in China (2010CI116, 2013FA046 and 2012FB177), National Natural Science Foundation of China (81373292), Outstanding Technical Talent Foundation and West Light Foundation of the Chinese Academy of Sciences.