Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins by Yongmei Xu, Kasemsiri Chandarajoti, Xing Zhang, Vijayakanth Pagadala,

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Presentation transcript:

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins by Yongmei Xu, Kasemsiri Chandarajoti, Xing Zhang, Vijayakanth Pagadala, Wenfang Dou, Debra Moorman Hoppensteadt, Erica M. Sparkenbaugh, Brian Cooley, Sharon Daily, Nigel S. Key, Diana Severynse-Stevens, Jawed Fareed, Robert J. Linhardt, Rafal Pawlinski, and Jian Liu Sci Transl Med Volume 9(406):eaan5954 September 6, 2017 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 1. Chemical structures and synthetic scheme of synthetic LMWHs, 12-mer-1 and 12-mer-2. Chemical structures and synthetic scheme of synthetic LMWHs, 12-mer-1 and 12-mer-2. (A) Chemical structures of 12-mer-1 and 12-mer-2. The name of each residue (A to L) is indicated at the top of the panel. The differences between two 12-mers are the number of 3-O-sulfo groups present: one in 12-mer-1 in residue C and two in 12-mer-2 in residues C and G (highlighted). pNP represents p-nitrophenyl group. (B) Synthetic schemes for 12-mer-1 and 12-mer-2 using shorthand symbols. Each reaction step uses different enzymes and chemicals: a, PmHS2 (heparosan synthase 2 from Pasteurella multocida) and UDP-GlcNTFA; b, PmHS2 and UDP-GlcA; c, LiOH; d, N-sulfotransferase (NST) and 3′-phosphoadenosine 5′-phosphosulfate (PAPS); e, C5-epimerase (C5-epi), 2-O-sulfotransferase (2-OST), and PAPS; f, 6-OST-1, 6-OST-3, and PAPS; g, 3-O-sulfotransferase isoform 1 (3-OST-1) and PAPS; h, 3-OST-5 and PAPS. Full synthetic schemes using chemical structures are shown in fig. S1. Yongmei Xu et al., Sci Transl Med 2017;9:eaan5954 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 2. In vitro, ex vivo, and in vivo analysis of the anticoagulant activity of 12-mers. In vitro, ex vivo, and in vivo analysis of the anticoagulant activity of 12-mers. (A) FXa inhibition curves of 12-mers and UFH in vitro. Data are means ± SD (n = 4). (B) Neutralization of FXa activity of 12-mers by protamine in vitro. In addition to 12-mers, UFH was included as a positive control, and fondaparinux and enoxaparin were included as negative controls. Data are means ± SD (n = 4). (C) Reversibility of anti-FXa activity by protamine in an ex vivo experiment. The statistical significance for the comparison of each sample with and without protamine is indicated (P < 0.001). (D) Reduction of clot weight in a venous thrombosis mouse model treated with PBS, enoxaparin, and 12-mer-1. (E) Plasma concentration of thrombin anti-thrombin (TAT) complexes and (F) FXa activity in control (AA) and sickle BERK (SS) mice injected with PBS or 12-mer-1 (2 mg/kg) subcutaneously every 8 hours for 7 days (n = 8 to 13). Blood was collected 2 hours after the last injection. Data are means ± SD. *P < 0.05, ***P < 0.001, ****P < 0.0001. n.s., not significant. Yongmei Xu et al., Sci Transl Med 2017;9:eaan5954 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 3. Clearance of 12-mer-1 in kidney I/R injury model in C57BL/6J mice. Clearance of 12-mer-1 in kidney I/R injury model in C57BL/6J mice. (A) Kidney I/R experimental scheme. (B) Plasma activity of FXa in mice subjected to kidney I/R injury (30 min of ischemia time followed by 24 hours of reperfusion) and injected subcutaneously with UFH (n = 6; 3 mg/kg), 12-mer-1 (n = 6; 1.5 mg/kg), or 12-mer-2 (n = 6; 0.3 mg/kg). (C) Plasma activity of FXa in sham-operated mice and mice subjected to different ischemia periods (20, 25, and 30 min). Mice received subcutaneous injection of PBS or 12-mer-1 (0.3 mg/kg) after 24 hours of reperfusion, and plasma was collected 2 hours later (n = 6 for each group). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Yongmei Xu et al., Sci Transl Med 2017;9:eaan5954 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 4. Clearance of 12-mer-1 from a nonhuman primate model. Clearance of 12-mer-1 from a nonhuman primate model. M. mulatta monkeys were treated with 12-mer-1 at a dose of 250 μg/kg either intravenously (IV) (A) or subcutaneously (SC) (B). Blood samples were collected before dosing (at t = 0 hour) and at 30, 60, and 120 min after dosing (for IV group) or at 1, 2, 4, and 6 hours after dosing (for SC group). The plasma concentration of 12-mer-1 was determined by measuring the activity of FXa, which was converted into the concentration of 12-mer-1 by a standard curve, as shown in fig. S21. Data are average ± range (n = 2). Yongmei Xu et al., Sci Transl Med 2017;9:eaan5954 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works