Synthesis and Biological Evaluation of a Unique Heparin Mimetic Hexasaccharide for Structure–Activity Relationship Studies

Roy, Sucharita; Hadri, Ahmed El; Richard, S.; Denis, Fanny; Holte, Kimberly; Duffner, Jay; Yu, Fei; Galcheva-Gargova, Zoya; Capila, Ishan; Schultes, Birgit C.; Petitou, Maurice; Kaundinya, Ganesh V.

doi:10.1021/jm4016069

Cited by 38 publications

(37 citation statements)

References 33 publications

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“…The new glycopolymers were then screened for their inhibition of heparanase using an in vitro TR-FRET assay against fluorescence-labeled heparan sulfate to test the effect of increased carbohydrate density and better mimicry of HS chains (diantennary vs monoantennary) 48 along with control glucosamine monosaccharide 33 and disaccharide 34 , as well as oligosaccharides 35 and 36 (Figure 5). 87–90 Glucosamine 33 bearing the sulfate group at C(6)- O and C(2)- N positions will be used to determine whether the glucuronic acid (GlcA) is important for inhibition against heparanase.…”

Section: Resultsmentioning

confidence: 99%

Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers

Sletten

Loka

et al. 2017

Biomacromolecules

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We report herein the first-time exploration of the attachment of well-defined saccharide units onto a synthetic polymer backbone for the inhibition of a glycosidase. More specifically, glycopolymers endowed with heparan sulfate (HS) disaccharides were established to inhibit the glycosidase, heparanase, with an IC50 value in the low nanomolar range (1.05 ± 0.02 nm), a thousand-fold amplification over its monovalent counterpart. The monomeric moieties of these glycopolymers were designed in silico to manipulate the well-established glycotope of heparanase into an inhitope. Studies concluded that (1) the glycopolymers are hydrolytic stable toward heparanase, (2) longer polymer length provides greater inhibition, and (3) increased local saccharide density (monoantennary vs diantennary) is negligible due to hindered active site of heparanase. Furthermore, HS oligosaccharide and polysaccharide controls illustrate the enhanced potency of a multivalent scaffold. Overall, the results on these studies of the multivalent presentation of saccharides on bottlebrush polymers serve as the platform for the design of potent glycosidase inhibitors and have potential to be applied to other HS-degrading proteins.

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Section: Resultsmentioning

confidence: 99%

Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers

Sletten

Loka

et al. 2017

Biomacromolecules

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“…CCL2, CCL11, and CXCL2 interact with a hexasacharide displaying a GlcNS6S-IdoA motif, but not with an otherwise similar molecule displaying a GlcNAc6S-IdoA2S motif. These studies also showed the importance of the 6-O-sulfation of the GlcN in high-affinity binding to CXCL12 [125]. Similarly, the chemical synthesis of heparin-like dodecasaccharides showed that a site-specific modification of the terminal GlcN affects a switch between inhibition of CXCL8 and CXCL12 [126].…”

Section: The Structures Recognized By Chemokinesmentioning

confidence: 87%

The sweet spot: how GAGs help chemokines guide migrating cells

Monneau

Arenzana-Seisdedos

Lortat‐Jacob

2015

Journal of Leukocyte Biology

115

113

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Glycosaminoglycans are polysaccharides that occur both at the cell surface and within extracellular matrices. Through their ability to bind to a large array of proteins, almost 500 of which have been identified to date, including most chemokines, these molecules regulate key biologic processes at the cell-tissue interface. To do so, glycosaminoglycans can provide scaffolds to ensure that proteins mediating specific functions will be presented at the correct site and time and can also directly contribute to biologic activities or signaling processes. The binding of chemokines to glycosaminoglycans, which, at the biochemical level, has been mostly studied using heparin, has traditionally been thought of as a mechanism for maintaining haptotactic gradients within tissues along which cells can migrate directionally. Many aspects of chemokine-glycosaminoglycan interactions, however, also suggest that the formation of these complexes could serve additional purposes that go well beyond a simple immobilization process. In addition, progress in glycobiology has revealed that glycosaminoglycan structures, in term of length, sulfation, and epimerization pattern, are specific for cell, tissue, and developmental stage. Glycosaminoglycan regulation and glycosaminoglycan diversity, which cannot be replicated using heparin, thus suggests that these molecules may fine-tune the immune response by selectively recruiting specific chemokines to cell surfaces. In this context, the aim of the present text is to review the chemokine-glycosaminoglycan complexes described to date and provide a critical analysis of the tools, molecules, and strategies that can be used to structurally and functionally investigate the formation of these complexes.

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“…TD4-143-1, which is a selectively sulfated tetrasaccharide containing unsubstituted glucosamine residues, which inhibited heparanase activity and suppressed invasion of breast cancer cells in vitro (163). Although not designed to specifically inhibit just heparanase, a newly synthesized hexasaccharide was considered to possess typical heparanase inhibition profile consistent with LMWHs and fondapariunx (164). Nevertheless, in both instances the anti-heparanase activity would be considered to be modest which perhaps limits the utility of such approaches in terms of preclinical or clinical development.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

Hammond¹,

et al. 2014

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Heparan sulfate proteoglycans (HSPGs) are an integral and dynamic part of normal tissue architecture at the cell surface and within the extracellular matrix. The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact cancer progression. As substrates for the key enzymes sulfatases and heparanase, the modification of HSPGs is typically characterized by the degradation of heparan sulfate (HS) chains/sulfation patterns via the endo-6-O-sulfatases (Sulf1 and Sulf2) or by heparanase, an endo-glycosidase that cleaves the HS polymers releasing smaller fragments from HSPG complexes. Numerous studies have demonstrated how these enzymes actively influence cancer cell proliferation, signaling, invasion, and metastasis. The activity or expression of these enzymes has been reported to be modified in a variety of cancers. Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease. Moreover, recent studies elucidating the requirements for these proteins in tumor initiation and progression exemplify their importance in the development and progression of cancer. Thus, as the influence of the tumor microenvironment in cancer progression becomes more apparent, the focus on targeting enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis. This review discusses the role of these enzymes in the context of the tumor microenvironment and their promise as therapeutic targets for the treatment of cancer.

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Synthesis and Biological Evaluation of a Unique Heparin Mimetic Hexasaccharide for Structure–Activity Relationship Studies

Cited by 38 publications

References 33 publications

Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers

Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers

The sweet spot: how GAGs help chemokines guide migrating cells

The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

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