title: Synthesis of a pseudo-disaccharide library and its application to the characterisation of the heparanase catalytic site.
abstract: A novel methodology is described for the efficient and divergent synthesis of pseudodisaccharides, molecules comprising of amino carbasugar analogues linked to natural sugars. The methodology is general and enables the introduction of diversity both at the carbasugar and the natural sugar components of the pseudodisaccharides. Using this approach, a series of pseudodisaccharides are synthesised that mimic the repeating backbone unit of heparan sulfate, and are tested for inhibition of heparanase, a disease-relevant enzyme that hydrolyses heparan sulfate. A new homology model of human heparanase is described based on a family 79 β-glucuronidase. This model is used to postulate a computational rationale for the observed activity of the different pseudodisaccharides and provide valuable information that informs the design of potential inhibitors of this enzyme.
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Vinader
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Haji-Abdullahi
authors.forename: L H
authors.initials: LH
authors.lastname: Patterson
authors.forename: Kamyar
authors.initials: K
authors.lastname: Afarinkia
mesh_terms: D020134:Catalytic Domain; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006497:Heparan Sulfate / Q000737:chemistry*; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D054852:Small Molecule Libraries; D000099175:Heparanase
chemical_list: D004187:Disaccharides; D004791:Enzyme Inhibitors; D005966:Glucuronidase; D006497:Heparan Sulfate; D054852:Small Molecule Libraries; D000099175:Heparanase