Dermatan Sulfate Epimerases (DSE, DSEL)

Maccarana, Marco; Malmström, Anders

doi:10.1007/978-4-431-54240-7_130

Cited by 1 publication

(1 citation statement)

References 44 publications

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“…To compare, a heparin pentasaccharide (fondaparinux) bearing an IdoA moiety, exhibited significantly higher activity against FXa (IC 50 = 11.0 ± 0.1 nM) and limited activity against FIIa. 40 Next, we screened the ability of trisaccharide 1α to bind to the HS-binding protein, platelet factor-4 (PF4), which is responsible for causing thrombocytopenia, [42][43] the main reason why clinical trials for other carbohydrate-based heparanase inhibitors were halted. [44][45] To achieve this goal, a solution-based biolayer interferometry (BLI) assay was utilized to determine the apparent K d of compound 1α to PF4 in comparison to biotinylated-heparin (18 kDa) attached to the BLI streptavidin-probe.…”

Section: Cross-bioactivity Studiesmentioning

confidence: 99%

Modulating Heparanase Activity: Tuning Sulfation Pattern and Glycosidic Linkage of Oligosaccharides

Zhu

Loka

et al. 2020

J. Med. Chem.

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Heparanase cleaves polymeric heparan sulfate (HS) molecules into smaller oligosaccharides, allowing for release of angiogenic growth factors promoting tumor development and autoreactive immune cells to reach the insulin-producing β cells. Interaction of heparanase with HS chains is regulated by specific substrate sulfation sequences. We have synthesized eleven trisaccharides that are highly tunable in structure and sulfation pattern, allowing us to determine how heparanase recognizes HS substrate and selects a favorable cleavage site. Our study shows that ( 1) N-SO 3 − at +1 subsite and 6-O-SO 3 − at −2 subsite of trisaccharides are critical for heparanase recognition; (2) addition of 2-O-SO 3 − at the −1 subsite and of 3-O-SO 3 − to GlcN unit is not advantageous; and (3) the anomeric configuration (α or β) at the reducing end is crucial in controlling heparanase activity. Our study also illustrates that the α-trisaccharide having Nand 6-O-SO 3 − at −2 and +1subsites inhibited heparanase and was resistant toward hydrolysis.

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