Title:
HEPARIN DODECASACCHARIDE CONTAINING DOUBLE ANTITHROMBIN BINDING SEQUENCE, PREPARATION METHOD THEREFOR, AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2024/032575
Kind Code:
A1
Abstract:
A heparin dodecasaccharide containing a double antithrombin binding sequence, a preparation method therefor, and use thereof. The heparin dodecasaccharide has a structure represented by formula I. Further provided are a chemoenzymatic preparation method for the compound having the structure represented by general formula I, and use thereof. The synthesis steps of the heparin dodecasaccharide are remarkably few, and the total yield is significantly high; the heparin dodecasaccharide has strong specific anti-Xa factor activity; the anti-Xa factor activity can be effectively neutralized by means of protamine with a neutralization rate greater than 80%; there is no a plurality of continuous disaccharide trisulfates, so that it is not easy to cause a pharmacokinetic defect (such as a short half-life period) and an adverse reaction (such as HIT) depending on the plurality of continuous disaccharide trisulfates (IdoA2S-GlcNS6S). The method is suitable for preparing a novel anti-coagulation and anti-thrombus medicament that is safer and has a remarkable cost advantage.
Inventors:
LIU CHUNHUI (CN)
ZHANG GUIJIAO (CN)
QIU YAQI (CN)
WANG LIN (CN)
LI JINGRU (CN)
ZHANG GUIJIAO (CN)
QIU YAQI (CN)
WANG LIN (CN)
LI JINGRU (CN)
Application Number:
PCT/CN2023/111623
Publication Date:
February 15, 2024
Filing Date:
August 08, 2023
Export Citation:
Assignee:
UNIV SHANDONG (CN)
International Classes:
C08B37/10; A61K31/727; A61P7/02; C12P19/18; C12P19/24; C12P19/26
Foreign References:
| CN115417937A | 2022-12-02 | |||
| CN113583151A | 2021-11-02 | |||
| CN101824100A | 2010-09-08 | |||
| CN105504097A | 2016-04-20 | |||
| CN110845641A | 2020-02-28 | |||
| CN112656808A | 2021-04-16 | |||
| US20130296540A1 | 2013-11-07 | |||
| US20190002596A1 | 2019-01-03 | |||
| US20210137967A1 | 2021-05-13 |
Other References:
VISKOV CHRISTIAN, ELLI STEFANO, URSO ELENA, GAUDESI DAVIDE, MOURIER PIERRE, HERMAN FREDERIC, BOUDIER CHRISTIAN, CASU BENITO, TORRI: "Heparin Dodecasaccharide Containing Two Antithrombin-binding Pentasaccharides", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, US, vol. 288, no. 36, 1 September 2013 (2013-09-01), US , pages 25895 - 25907, XP093139286, ISSN: 0021-9258, DOI: 10.1074/jbc.M113.485268
WEIHUA JIN ET AL.: "Bioengineered production of glycosaminoglycans and their analogues", SYSTEMS MICROBIOLOGY AND BIOMANUFACTURING, no. 1, 17 August 2020 (2020-08-17), XP09552621
ZHANG CHENGYING; TANG FENGYAN; ZHANG JINGJING; CAO JICHAO; LI HUIJUAN; LIU CHUNHUI: "Uncovering the detailed mode of cleavage of heparinase I toward structurally defined heparin oligosaccharides", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, ELSEVIER BV, NL, vol. 141, 31 August 2019 (2019-08-31), NL , pages 756 - 764, XP086037583, ISSN: 0141-8130, DOI: 10.1016/j.ijbiomac.2019.08.260
HU GUIXIN; SHAO MENG; GAO XIN; WANG FENGSHAN; LIU CHUNHUI: "Probing cleavage promiscuity of heparinase III towards chemoenzymatically synthetic heparan sulfate oligosaccharides", CARBOHYDRATE POLYMERS, APPLIED SCIENCE PUBLISHERS , LTD BARKING, GB, vol. 173, 26 May 2017 (2017-05-26), GB , pages 276 - 285, XP085134536, ISSN: 0144-8617, DOI: 10.1016/j.carbpol.2017.05.071
LIU CHUNHUI, SHENG JUZHENG, KRAHN JUNO M., PERERA LALITH, XU YONGMEI, HSIEH PO-HUNG, DOU WENFANG, LIU JIAN, PEDERSEN LARS C.: "Molecular Mechanism of Substrate Specificity for Heparan Sulfate 2-O-Sulfotransferase", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, US, vol. 289, no. 19, 1 May 2014 (2014-05-01), US , pages 13407 - 13418, XP093139289, ISSN: 0021-9258, DOI: 10.1074/jbc.M113.530535
ZHANG, GUIJIAO: "Study on Chemoenzymatic Synthesis of Unmodified Heparin Oligosaccharides and Preliminary Anticoagulant Activity", MASTER’S THESES, SHAN DONG UNIVERSITY, CHINA, no. 9, 27 May 2021 (2021-05-27), China, XP009552622, DOI: 10.27272/d.cnki.gshdu.2021.001186
WEIHUA JIN ET AL.: "Bioengineered production of glycosaminoglycans and their analogues", SYSTEMS MICROBIOLOGY AND BIOMANUFACTURING, no. 1, 17 August 2020 (2020-08-17), XP09552621
ZHANG CHENGYING; TANG FENGYAN; ZHANG JINGJING; CAO JICHAO; LI HUIJUAN; LIU CHUNHUI: "Uncovering the detailed mode of cleavage of heparinase I toward structurally defined heparin oligosaccharides", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, ELSEVIER BV, NL, vol. 141, 31 August 2019 (2019-08-31), NL , pages 756 - 764, XP086037583, ISSN: 0141-8130, DOI: 10.1016/j.ijbiomac.2019.08.260
HU GUIXIN; SHAO MENG; GAO XIN; WANG FENGSHAN; LIU CHUNHUI: "Probing cleavage promiscuity of heparinase III towards chemoenzymatically synthetic heparan sulfate oligosaccharides", CARBOHYDRATE POLYMERS, APPLIED SCIENCE PUBLISHERS , LTD BARKING, GB, vol. 173, 26 May 2017 (2017-05-26), GB , pages 276 - 285, XP085134536, ISSN: 0144-8617, DOI: 10.1016/j.carbpol.2017.05.071
LIU CHUNHUI, SHENG JUZHENG, KRAHN JUNO M., PERERA LALITH, XU YONGMEI, HSIEH PO-HUNG, DOU WENFANG, LIU JIAN, PEDERSEN LARS C.: "Molecular Mechanism of Substrate Specificity for Heparan Sulfate 2-O-Sulfotransferase", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, US, vol. 289, no. 19, 1 May 2014 (2014-05-01), US , pages 13407 - 13418, XP093139289, ISSN: 0021-9258, DOI: 10.1074/jbc.M113.530535
ZHANG, GUIJIAO: "Study on Chemoenzymatic Synthesis of Unmodified Heparin Oligosaccharides and Preliminary Anticoagulant Activity", MASTER’S THESES, SHAN DONG UNIVERSITY, CHINA, no. 9, 27 May 2021 (2021-05-27), China, XP009552622, DOI: 10.27272/d.cnki.gshdu.2021.001186
Attorney, Agent or Firm:
JINAN JINDI INTELLECTUAL PROPERTY AGENCY CO., LTD et al. (CN)
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