Synthesis of 3-O-sulfonated heparan sulfate octasaccharides that inhibit the herpes simplex virus type 1 host–cell interaction

Hu, Yu‐Peng; Lin, Shu‐Yi; Huang, Cheng‐Yen; Zulueta, Medel Manuel L.; Liu, Jing-Yuan; Chang, Wen; Hung, Shang‐Cheng

doi:10.1038/nchem.1073

Cited by 170 publications

(106 citation statements)

References 37 publications

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“…1). Unlike the N-sulfo-oligosaccharides, a mixture of oligosaccharides was obtained after O-sulfations and C 5 -epimerization (9). We observed that the products were eluted as a broad peak on DEAE-HPLC (supplemental Fig.…”

Section: Preparation Of Oligosaccharides Carrying Idoua Residues and mentioning

confidence: 85%

“…A cost-effective method for preparing synthetic heparin and securing the safety of the heparin supply chain is highly desirable. Although heparin and HS fragments can be synthesized by a purely chemical method (8,9), this synthesis is extremely challenging, especially for products larger than an octasaccharide. A new chemoenzymatic approach provides a promising alternative method to synthesize polysaccharides and structurally defined oligosaccharides (10 -14).…”

Section: Heparan Sulfate (Hs)mentioning

confidence: 99%

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Chemoenzymatic Synthesis of Heparin Oligosaccharides with both Anti-factor Xa and Anti-factor IIa Activities

Pempe

Liu

2012

Journal of Biological Chemistry

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Background: Heparin inhibits the activity of factors Xa and IIa in the blood coagulation cascade. Results: A series of size-defined N-sulfated oligosaccharides were synthesized to probe the size requirement for the oligosaccharides displaying anti-IIa activity. Conclusion: Oligosaccharides that display anti-IIa activity are longer than 19 saccharide residues. Significance: The results will direct efforts to prepare synthetic heparin with both anti-Xa and anti-IIa activities.

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Section: Preparation Of Oligosaccharides Carrying Idoua Residues and mentioning

confidence: 85%

Section: Heparan Sulfate (Hs)mentioning

confidence: 99%

Chemoenzymatic Synthesis of Heparin Oligosaccharides with both Anti-factor Xa and Anti-factor IIa Activities

Pempe

Liu

2012

Journal of Biological Chemistry

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“…The proof of principle for SDC1 as a viable target was first demonstrated by the findings that a recombinant SDC1-Fc fusion protein expressed in CHO cells could potently block HIV infection of T cells, macrophages, and dendritic cells as well as HSV-1 infection (76). Recently, 3-Osulfonated HS octasaccharides were synthesized and were shown to have antiviral activity inhibiting HSV-1 infection (77). It is anticipated that recombinant SDCs, HS mimetics, and/or smallmolecule inhibitors can be developed as prophylactic and/or therapeutic agents for different viruses.…”

Section: Discussionmentioning

confidence: 99%

Syndecan-1 Serves as the Major Receptor for Attachment of Hepatitis C Virus to the Surfaces of Hepatocytes

Shi

Jiang

Luo

2013

J Virol

107

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cOur recent studies demonstrated that apolipoprotein E mediates cell attachment of hepatitis C virus (HCV) through interactions with the cell surface heparan sulfate (HS). HS is known to covalently attach to core proteins to form heparan sulfate proteoglycans (HSPGs) on the cell surface. The HSPG core proteins include the membrane-spanning syndecans (SDCs), the lycosylphosphatidylinositol-linked glypicans (GPCs), the basement membrane proteoglycan perlecan (HSPG2), and agrin. In the present study, we have profiled each of the HSPG core proteins in HCV attachment. Substantial evidence derived from our studies demonstrates that SDC1 is the major receptor protein for HCV attachment. The knockdown of SDC1 expression by small interfering RNA (siRNA)-induced gene silence resulted in a significant reduction of HCV attachment to Huh-7.5 cells and stem cell-differentiated human hepatocytes. The silence of SDC2 expression also caused a modest decrease of HCV attachment. In contrast, the siRNA-mediated knockdown of other SDCs, GPCs, HSPG2, and agrin had no effect on HCV attachment. More importantly, ectopic expression of SDC1 was able to completely restore HCV attachment to Huh-7.5 cells in which the endogenous SDC1 expression was silenced by specific siRNAs. Interestingly, mouse SDC1 is also fully functional in mediating HCV attachment when expressed in the SDC1-deficient cells, consistent with recent reports that mouse hepatocytes are also susceptible to HCV infection when expressing other key HCV receptors. Collectively, our findings demonstrate that SDC1 serves as the major receptor protein for HCV attachment to cells, providing another potential target for discovery and development of antiviral drugs against HCV. H epatitis C virus (HCV) is a common cause of chronic liver diseases such as hepatitis, cirrhosis, and liver cancer. It is an enveloped RNA virus containing a single positive-sense RNA genome that encodes a polyprotein precursor of 3,000 amino acids (1). Upon translation, the viral polyprotein was cleaved by cellular peptidases, viral NS2/NS3 metalloprotease, and NS3/4A serine protease to produce mature HCV structural (C, E1, and E2) and nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (2, 3). The untranslated nucleotide sequences flanked at both the 5= and 3= ends of the HCV RNA genome are highly conserved and form complex secondary and tertiary structures serving as cis-acting RNA elements important for initiation of viral protein translation and/or viral RNA replication. Based on the common features of viral RNA genome organization, HCV is classified in the Hepacivirus genus of the Flaviviridae family (4, 5).HCV enters cells via receptor-mediated endocytosis (6). A number of cell surface proteins were shown to interact with the viral envelope glycoproteins E1 and E2 (7). Human CD81 was identified as the first HCV receptor/coreceptor (8). Subsequently, many other cell surface proteins were found to be important for HCV cell entry (9), including the low-density lipoprotein receptor (LDL...

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“…A number of oligosaccharides are synthesized via a purely organic synthetic approach 11–15 , but it is still very difficult to synthesize oligosaccharides larger than hexasaccharides with complex sulfation patterns. As an alternative approach, a chemoenzymatic method to synthesize HS oligosaccharides has emerged, using HS biosynthetic enzymes involving glycosyltransferases, C 5 -epimerase, and sulfotransferases 16–17 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Wang

Hsieh

et al. 2017

J. Am. Chem. Soc.

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The sulfation at the 3-OH position of glucosamine is an important modification in forming structural domains for heparan sulfate to enable its biological functions. Seven 3-O-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3-O-sulfated heparan sulfate. As a rare modification present in heparan sulfate, the availability of 3-O-sulfated oligosaccharides is very limited. Here, we report the use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis was achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O-sulfotransferase 3. We studied the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR, and on the correlation between ring conformation and anticoagulant activity. We identified a novel octasaccharide that interacts with antithrombin and displays anti factor Xa activity. Interestingly, the octasaccharide displays a faster clearance rate than fondaparinux, an FDA approved pentasaccharide drug, in a rat model, making this octasaccharide a potential short acting anticoagulant drug candidate that could reduce bleeding risk. Having access to a set of critically important 3-O-sulfated oligosaccharides offers the potential to develop new heparan sulfate-based therapeutics.

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Synthesis of 3-O-sulfonated heparan sulfate octasaccharides that inhibit the herpes simplex virus type 1 host–cell interaction

Cited by 170 publications

References 37 publications

Chemoenzymatic Synthesis of Heparin Oligosaccharides with both Anti-factor Xa and Anti-factor IIa Activities

Chemoenzymatic Synthesis of Heparin Oligosaccharides with both Anti-factor Xa and Anti-factor IIa Activities

Syndecan-1 Serves as the Major Receptor for Attachment of Hepatitis C Virus to the Surfaces of Hepatocytes

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

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