Design and Synthesis of Neutralizable Fondaparinux

Liangwei Zhang; Yating Liu; Zhuojia Xu; Tianhui Hao; Peng George Wang; Wei Zhao; Tiehai Li

doi:10.1021/jacsau.2c00537

Design and Synthesis of Neutralizable Fondaparinux

JACS Au. 2022 Nov 14;2(12):2791-2799. doi: 10.1021/jacsau.2c00537. eCollection 2022 Dec 26.

Authors

Liangwei Zhang¹, Yating Liu^{1

2}, Zhuojia Xu^{1

3}, Tianhui Hao^{1

3}, Peng George Wang⁴, Wei Zhao⁵, Tiehai Li^{1

2

3

6}

Affiliations

¹ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
⁵ College of Pharmacy, Nankai University, Tianjin 300353, China.
⁶ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan University, Chengdu 610041, China.

Abstract

Fondaparinux, a clinically approved anticoagulant pentasaccharide for the treatment of thrombotic diseases, displays better efficacy and biosafety than other heparin-based anticoagulant drugs. However, there is no suitable antidote available for fondaparinux to efficiently manage its potential bleeding risks, thereby precluding its widespread use. Herein, we describe a convergent and stereocontrolled approach to efficiently synthesize an aminopentyl-functionalized pentasaccharide, which is further used to prepare fondaparinux-based biotin conjugates and clusters. Biological activity evaluation demonstrates that the anticoagulant activity of the fondaparinux-based biotin conjugate and trimer is, respectively, neutralized by avidin and protamine as effective antidotes. This work suggests that our synthetic biotin conjugate and trimer have potential for the development of neutralizable and safe anticoagulant drugs.