School of Pharmaceutical Sciences, South-Central University for Nationalities, 182 Minzu Road, Wuhan 430074, Hubei, China
E-mail: zhaojinhua@mail.kib.ac.cn
Education
1996.6-1999.6: Ph.D., Zoology (Natural Pharmacy), School of Life Sciences, Sun Yat-sen University
1993.9-1996.6: M.Sc., Physiology (Cardiovascular Pharmacology), School of Life Sciences, Sun Yat-sen University
1988.9-1990.6: B.Sc. Department of Biology, Anhui Education College
1981.9-1984.6: Study in Wuwei Normal School, Anhui Province.
Professional Experiences
2015-present: Professor, Institute of Pharmacology, School of Pharmaceutical Sciences, South-Central University for Nationalities
2010-2018: Professor, Kunming Institute of Botany, Chinese Academy of Sciences
1999-2010: Senior Manager & Senior Researcher, Technology Center of Shenzhen Neptunus Group Co., Ltd.
1984-1993: Taiping Junior Highschool, Wuwei County, Anhui Province.
Team
Dr. Zhao Longyan, Lecturer
Dr. Gao Na, Lecturer
Research Interests
Evaluation of the activity of natural products on cardiovascular system, investigation of the mechanism of these active compounds, and discovery and development of new drugs.
Recently, our research focuses on investigation of the precise chemical structure and structural modification of complex natural polysaccharides with repetitive structural units, their cardiovascular activity, pharmacological mechanisms and structure-activity relationships.
Major Research Progress
In the chemical and pharmacological researches on fucosylated glycosaminoglycan (FG), we established several depolymerization methods which could highly-selectively cleave the special glycosidic bonds in FG backbone. Based on the bottom up strategy, the precise structures of native FGs from various species of sea cucumber have been well-defined by the preparation of depolymerized products and the purification and structural analysis of the resulting oligosaccharides. A series of pure FG-derived oligosaccharides with different reducing or non-reducing end residues and their derivatives with structural modification were obtained for investigation of the pharmacological activity and structure-activity relationships.
By systematically evaluating the anticoagulant and antithrombotic activities of native FG, its depolymerized products and pure oligosaccharides, we elucidated the structure-activity relationship and essential structural characteristics of FG fragments for selective and potent inhibition of intrinsic factor tenase complex (F.Xase), and also elucidated the F.Xase inhibition mechanisms of FG by investigation of tenase enzymatic kinetics in the presence of FG oligosaccharides and by investigation of the affinity and dynamic processes of interaction of FG with the target protein.
Based on the anticoagulant activity of native FGs and their derivatives, a new anti-coagulant and anti-thrombotic drug, LFG (novel chemical entity), which is a potent and selective inhibitor of intrinsic Xase, is in preclinical development under combination with a famous pharmaceutical company. Compared with enoxaparin which is a clinical first-line drug, LFG has the advantage of lower risk of bleeding. A series of pertinent patents related to LFG have been authorized by China, the United States, Japan and other countries.
During the period in the National Technology Center of Shenzhen Neptunus Group Co., Ltd., I was responsible for innovative drug research and development and established an experimental research platform for drug discovery. The representative achievements include: a State first class new drug - Polydatin Injection (approved for clinical trials by the CFDA and FDA), a fifth class new drug - Aixintong Tablets (approved for clinical trials by the Chinese FDA), improvement of a Traditional Chinese medicine -Biyuan Soft Capsule (licensed for marketing) and etc.
More than 70 papers have been published in domestic and international academic journals such as PNAS, JBC, Eur J Med Chem, Thromb Haemost, Carbohydr Polym, BBA, Angew Chem Int Ed, Chem Eur J, Thromb Res, Mar Drugs, etc. More than 60 patents have been applied, among which, more than 50 invention patents have been authorized by China, the United States, Japan, Australia, and other countries.
Our research projects are supported by more than twenty foundations, with resources from Nation, Academy and Province, including the National Major Special Project for “Significant New Drugs Development”, the 863 Project and the Guiding Project, the Major Project of the National Development and Reform Commission, the Technology Innovation Project of the Ministry of Science and Technology, the Innovative Medicine Project of the CAS Chinese Academy of Sciences, the Natural Product Application Transformation Project of the CAS Chinese Academy of Sciences, the Key breakthrough projects in key areas of Guangdong and Hong Kong, the Shenzhen-Hong Kong Innovation Circle Project, the Guangdong Province Ministry of Education Industry-University-Research Project, the Key Project of Yunnan Province Applied Basic Research Program, and the Yunnan Key New Product Project.
Selected Recent Publications:
[1]Yin RH, Zhou LT, Gao N, Li Z, Zhao LY, Shang FN, Wu MY*, Zhao JH*. Oligosaccharides from depolymerized fucosylated glycosaminoglycan: Structures and minimum size for intrinsic factor Xase complex inhibition. J Biol Chem. 2018; 293(36): 14089-14099.
[2]Zhao LY, Qin YJ, Guan RW, Zheng WQ, Liu JK, Zhao JH*. Digestibility of fucosylated glycosaminoglycan from sea cucumber and its effects on digestive enzymes under simulated salivary and gastrointestinal conditions.Carbohyd Polym. 2018; 186: 217-225.
[3]Xu L, Gao N, Xiao C, Lin LS, Purcell SW, Wu MY*, Zhao JH*. Modulating the degree of fucosylation of fucosylated chondroitin sulfate enhances heparin cofactor II-dependent thrombin inhibition. Eur J Med Chem. 2018; 154:133-143.
[4]Cai Y, Yang WJ, Yin RH, Zhou LT, Li ZK, Wu MY*, Zhao JH*. An anticoagulant fucan sulfate with hexasaccharide repeating units from the sea cucumber Holothuria albiventer. Carbohyd Res, 2018; 464: 12-18.
[5]Shang FN, Mou RR, Zhang ZD, Gao N, Lin LS, Li ZK, Wu MY*, Zhao JH*. Structural analysis and anticoagulant activities of three highly regular fucan sulfates as novel intrinsic factor Xase inhibitors. Carbohyd Polym. 2018; 195: 257-266.
[6]Shang FN, Gao N, Yin RH, Lin LS, Xiao C, Zhou LT, Li Z, Purcell SW, Wu MY*, Zhao JH*.Precise structures of fucosylated glycosaminoglycan and its oligosaccharides as novel intrinsic factor Xase inhibitors. Eur J Med Chem. 2018;148: 423-435.
[7]Liu J, Zhou LT, He ZC, Gao N, Shang FN, Xu JP, Li Z, Yang ZM, Wu MY*, Zhao JH*. Structural analysis and biological activity of a highly regular glycosaminoglycan from Achatina fulica. Carbohyd Polym. 2018; 181: 433-441.
[8]Qin YJ, Yuan QX, Zhang YX, Li JL, Zhu XJ, Zhao LL, Wen J, Liu JK, Zhao LY*, Zhao JH*. Enzyme-assisted extraction optimization, characterization and antioxidant activity of polysaccharides from sea cucumber Phyllophorus proteus.Molecules. 2018; 23: 590-609.
[9]Zhang X, Yao W, Xu XJ, Sun HF, Zhao JH, Meng XB, Wu MY, Li ZJ*. Synthesis of fucosylated chondroitin sulfate glycoclusters: a robust route to new anticoagulant agents. Chem-Eur J. 2018; 24(7): 1694-1700.
[10]Zhang X, Liu H, Lin L, Yao W, Zhao JH, Wu MY*, Li ZJ*. Synthesis of fucosylated chondroitin sulfate nonasaccharide as a novel anticoagulant targeting intrinsic factor Xase complex. Angew Chem Int Ed. 2018; 57(39): 12880-12885.
[11]Li XM, Luo L, Cai Y, Yang WJ, Lin LS, Li Z, Gao N, Purcell SW, Wu MY*, Zhao JH*. Structural elucidation and biological activity of a highly regular fucosylated glycosaminoglycan from the edible sea cucumber Stichopus herrmanni. J Agric Food Chem. 2017; 65(42): 9315-9323.
[12]Xiao C, Lian W, Zhou LT, Gao N, Xu L, Chen J, Wu MY*, Peng WL*, Zhao JH*. Interactions between depolymerized fucosylated glycosaminoglycan and coagulation proteases or inhibitors,Thromb Res. 2016; 146: 59-68.
[13]Zhao LY, Wu MY, Xiao C, Yang L, Zhou LT, Gao N, Li Z, Chen J, Chen JC, Liu JK*, Qin HB*, Zhao JH*. Discovery of an intrinsic tenase inhibitor, pure nonasaccharide from fucosylated glycosaminoglycan.PNAS. 2015; 112: 8284-8289.
[14]Wu MY, Wen DD, Gao N, Xiao C, Yang L, Xu L, Lian W, Peng WL, Jiang JM*, Zhao JH*. Anticoagulant and antithrombotic evaluation of native fucosylated chondroitin sulfates and their derivatives as selective inhibitors of intrinsic factor Xase. Eur J Med Chem. 2015; 92: 257-269.
[15]Gao N, Lu F, Xiao C, Yang L, Chen J, Zhou K, Wen DD, Li Z, Wu MY, Jiang JM, Liu GM*,Zhao JH*. β-Eliminative depolymerization of the fucosylated chondroitin sulfate and anticoagulant activities of resulting fragments. Carbohyd Polym. 2015; 127(3): 427-437.
[16]Wu MY, Xu L, Zhao LY, Xiao C, Gao N, Luo L, Yang L, Li Z, Chen LY,* Zhao JH*. Structural analysis and anticoagulant activities of the novel sulfated fucan possessing a regular well-defined repeating unit from Sea Cucumber. Mar Drugs.2015; 13: 2063-2084.
[17]Lian W, Huang N, Li Z, Zheng YT*, Peng WL*, Zhao JH*. Anti-HIV-1 activity and structure-activity-relationship study of a fucosylated glycosaminoglycan from an echinoderm by targeting the conserved CD4 induced epitope. Biochim Biophys Acta. 2013; 1830: 4681-4691.
[18]Zhao LY, Lai SS, Huang R, Wu MY, Gao N, Xu L, Qin HB*, Peng WL*, Zhao JH*. Structure and anticoagulant activity of fucosylated glycosaminoglycan degraded by deaminative cleavage. Carbohyd Polym. 2013; 98(2): 1514-1523.
[19]Luo L, Wu MY, Xu L, Lian W, Xiang JY, Lu F, Gao N, Zhao JH*. Comparison of physicochemical characteristics and anticoagulant activities of polysaccharides from three sea cucumbers. Mar Drugs. 2013; 11: 399-417.
[20]Huang N, Wu MY, Zheng CB, Zhu L, Zhao JH*, Zheng YT*. The depolymerized fucosylated chondroitin sulfate from sea cucumber potently inhibits HIV replication via interfering with virus entry. Carbohyd Res. 2013; 380: 64-69.
Selected Authorized Invention Patent:
[1]Zhao JH, Liu JK, Wu MY, Gao N, Lu F, Li Z. Low molecular weight glycosaminoglycan derivative, pharmaceutical composition thereof, preparation method therefor and use thereof. US 9896517b2 [The United States authorized, 2018-02-20]
[2]Zhao JH, Liu JK, Wu MY, Gao N, Lu F, Li Z. Low-molecular-weight-glycosaminoglycan derivative, pharmaceutical composition thereof, preparation method therefor and use thereof. License 6293862 [Japan authorized, 2018-02-23]
[3]Zhao JH, Wu MY, Gao N, Li Z, Lai SS, Zhao LY. Low-molecular-weight- glycosaminoglycan derivative containing terminal 2,5-anhydrated talose or derivate thereof. License 6248179 [Japan authorized, 2017-11-24]
[4]Zhao JH, Kang H, Wu MY, Zeng WZ, Li Z, Gao Y, Cui J, Wang ZG, Feng HL, Yu, L. Depolymerized glycosaminoglycan from Thelenota ananas and preparation method thereof. AUS 2010324437 [Australian authorized, 2015-04-02].
[5]Zhao JH, He JX, Wu MY, Liu ZW, Gao N, Zhao LY, Li Z, Lu F, Xu L, Xiao C, Yang L, Chen J, Zhou LT, Peng WL, Liu JK. Fuc3S4S substituted oligoglycosaminoglycan and preparation method thereof. WO 2015/103921 A1
[6]Zhao JH, Liu JK, Wu MY, Gao N, Lu F, Li Z. Derivate of low molecular weight fucosylated glycosaminoglycan and medical composition and preparation method and application thereof. CN 103145868 B
[7]Liu JK, Zheng YT, Zhao JH, Wu MY, Huang N, Li Z, Gao N, Wen DD, Lian W, He JB. Low molecular weight carboxyl-reduced derivatives of fucosylated glycosaminoglycans and preparation method and applications of low molecular weight carboxyl-reduced derivatives. CN 102558389 B
[8]Zhao JH, Wu MY, Li Z. Composition containing dendrobium polysaccharide and atractylodes oil and application thereof. CN 103690582 B
[9]Zhao JH, Wu MY, Gao N, Wen DD, Lian W, Li Z. Fucosylated glycosaminoglycan derivative and preparation method thereof. CN 102329397 B
[10]Zhao JH, Wu MY, Li Z. Composition for treating digestive ulcer and applications thereof. CN 103735591 B
[11]Zhao JH, He JX, Wu MY, Zhao LY, Liu ZW, Yang L, Li Z, Gao N, Xiao C, Xu L, Chen J, Zhou LT. Oligosaccharide compound inhibiting endogenous factor X enzyme activity and pharmaceutical composition thereof. CN 104370980 B
[12]Zhao JH, Wu MY, Gao N, Li Z, Lai SS, Zhao LY. 2,5-anhydrated talose or derivatives thereof terminal low-molecular-weight glycosaminoglycan derivative. CN 103214591 B
[13]Zhao JH, He JX, Wu MY, Liu ZW, Gao N, Zhao LY, Li Z, Lu F, Xu L, Xiao C, Yang L, Chen J, Zhou LT, Peng WL, Liu JK. Fuc3S4S substituted oligo-glycosaminoglycan and preparation method thereof. CN 103788222 B
Awards and Recognition
lOutstanding scientific and technological talents in the pharmaceutical industry of Guangdong Province for 30 years of reform and opening up (2008)
lYunnan high-end talent program (2010)
lHundred talent program of CAS (2011)
lAcademic research on F.Xase inhibitors was selected into the “Top Ten Progress” of Kunming Institute of Botany, Chinese Academy of Sciences (2015)
lNew drug technology transfer of LFG was selected into the “Top Ten Progress” (First Place) of Kunming Institute of Botany (2016)
lThe special allowance of Yunnan provincial government (2017)
