Chemoenzymatic synthesis and structural characterization of 2-O-sulfated glucuronic acid-containing heparan sulfate hexasaccharides

Hsieh, Po Hung; Xu, Yongmei; Keire, David A.; Liu, Jian

doi:10.1093/glycob/cwu032

Cited by 32 publications

(43 citation statements)

References 37 publications

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“…The synthesis of 12-mer-1 and 12-mer-2 was completed according to the chemoenzymatic method published previously (12, 45). Briefly, PmHS2 from P. multocida was used in conjunction with UDP-sugars to elongate the monosaccharide, GlcA-pNP, to appropriate-sized backbones.…”

Section: Methodsmentioning

confidence: 99%

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

Chandarajoti

Zhang

et al. 2017

Sci. Transl. Med.

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Low–molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs.

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Section: Methodsmentioning

confidence: 99%

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

Chandarajoti

Zhang

et al. 2017

Sci. Transl. Med.

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“…Protocols for synthesizing HS oligosaccharide on the basis of chemoenzymatic reactions have been established . Comprehensive reviews in the area have been published .…”

Section: Synthetic Gagsmentioning

confidence: 99%

“…B), and the deca‐, undeca‐, and dodecasaccharides containing the GlNS3S6S units . Another example is the 2‐ O ‐sulfated GlcA‐containing HS hexasaccharides recently produced by Hsieh and co‐workers . As seen for the modular‐based synthesis of HS oligosaccharides, fluorous tag can be also fruitfully used in chemoenzymatic‐based synthesis of HS tetrasaccharide and hexasaccharide .…”

Section: Synthetic Gagsmentioning

confidence: 99%

A Dilemma in the Glycosaminoglycan‐Based Therapy: Synthetic or Naturally Unique Molecules?

Pomin

2015

Medicinal Research Reviews

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Glycosaminoglycans (GAGs) are widely explored in the biomedical market as functional ingredients in pharmaceutical or nutraceutical preparations. This extensive application of GAGs is justified by their multiple activities across several systems including, but not limited to, coagulation, thrombosis, inflammation, cancer, angiogenesis, cell differentiation, tissue repair, and microbial infections. Therapeutic GAGs are commonly extracted from mammalian tissues. Although functional in diverse systems, mammalian GAGs present serious downsides in therapy such as contamination risk from the mammalian tissues. In order to overcome some of the downsides, two new GAG sources have been appearing as alternatives to the mammalian-derived molecules. They are the synthetic GAGs and those extracted from nonmammalian origins such as invertebrate animals. This report overviews the general aspects of each GAG alternative and compares critically their pros and cons attributes in light of the prospects for the future of GAG-based therapy.

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“…Recent studies show that chemoenzymatically prepared HS hexasaccharides containing one GlcAp2S residue do not bind to AT. 46 Thus, we posit that the reason HS 2S2S binds and activates AT so well is because of the presence of several GlcAp2S residues within the serpin binding domain. The presence of several GlcAp2S units may enhance the probability of interaction with AT in a statistical manner or may enhance the selectivity of binding to AT because of a simultaneous engagement of two or more GlcAp2S residues.…”

Section: ■ Discussionmentioning

confidence: 94%

Chemoenzymatically Prepared Heparan Sulfate Containing Rare 2-O-Sulfonated Glucuronic Acid Residues

Boothello

Sarkar

Tran³

et al. 2015

ACS Chem. Biol.

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The structural diversity of natural sulfated glycosaminoglycans (GAGs) presents major promise for discovery of chemical biology tools or therapeutic agents. Yet, few GAGs have been identified so far to exhibit this promise. We reasoned that a simple approach to identify such GAGs is to explore sequences containing rare residues, for example, 2-O-sulfonated glucuronic acid (GlcAp2S). Genetic algorithm-based computational docking and filtering suggested that GlcAp2S containing heparan sulfate (HS) may exhibit highly selective recognition of antithrombin, a key plasma clot regulator. HS containing only GlcAp2S and 2-N-sulfonated glucosamine residues, labeled as HS 2S2S , was chemoenzymatically synthesized in just two steps and was found to preferentially bind antithrombin over heparin cofactor II, a closely related serpin. Likewise, HS 2S2S directly inhibited thrombin but not factor Xa, a closely related protease. The results show that a HS containing rare GlcAp2S residues exhibits the unusual property of selective antithrombin activation and direct thrombin inhibition. More importantly, HS 2S2S is also the first molecule to activate antithrombin nearly as well as the heparin pentasaccharide although being completely devoid of the critical 3-O-sulfonate group. Thus, this work shows that novel functions and mechanisms may be uncovered by studying rare GAG residues/sequences. S ulfated glycosaminoglycans (GAGs), natural linear copolymers of hexuronic acid and hexosamine residues, represent nature's bounty of chemical biology tools and therapeutic agents. Despite this, the current state-of-art displays minimal exploitation of this promise. Few GAG-based agents have been used to elucidate new pathways and very few GAG-based agents, other than polymeric heparin and dermatan sulfate, have reached the clinic. A major challenge in realizing the true biochemical and pharmacologic potential of GAGs is the structural microheterogeneity present in the GAGs isolated from tissues or cells. The variations introduced by nontemplate-driven sulfation, deacetylation, and epimerization reactions during their biosynthesis, 1,2 coupled with the postsynthetic fine-tuning of their structure by sulfatases, 3 generate millions of distinct sequences that pose significant challenges for detailed structural analysis.Despite these challenges, sulfated GAGs are very attractive as potential seeds for new drugs. The presence of O-sulfonate ( OSO 3¯) groups on a GAG chain induces recognition and modulation of most proteins, especially those that display a collection of arginine and lysine residues on their surface. This gives rise to GAG modulation of a large number of physiological and pathological responses such as growth and cancer, cell renewal and differentiation, hemostasis and fibrinolysis, inflammation and immune response, and microbial invasion and defense. 2 It is likely that individual proteins bind to only a subset of GAG sequences from the natural repertoire of millions. A classic example of this high selectivity is the heparin pentasa...

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Chemoenzymatic synthesis and structural characterization of 2-O-sulfated glucuronic acid-containing heparan sulfate hexasaccharides

Cited by 32 publications

References 37 publications

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

A Dilemma in the Glycosaminoglycan‐Based Therapy: Synthetic or Naturally Unique Molecules?

Chemoenzymatically Prepared Heparan Sulfate Containing Rare 2-O-Sulfonated Glucuronic Acid Residues

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