title: A Hexasaccharide Containing Rare 2-O-Sulfate-Glucuronic Acid Residues Selectively Activates Heparin Cofactor II.
abstract: Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2-O-sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250-fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG-binding protein(s), which may lead to chemical biology or drug discovery tools.
authors.affiliation: Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Nehru Viji
authors.identifier: 0000-0002-2870-9164
authors.initials: NV
authors.lastname: Sankarayanarayanan
authors.affiliation: Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland.
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Strebel
authors.affiliation: Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Rio S
authors.initials: RS
authors.lastname: Boothello
authors.affiliation: Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Sheerin
authors.affiliation: Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Raghuraman
authors.affiliation: Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland.
authors.forename: Florence
authors.initials: F
authors.lastname: Sallas
authors.affiliation: Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.affiliation: Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Watermeyer
authors.affiliation: Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oscarson
authors.affiliation: Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Umesh R
authors.identifier: 0000-0002-1976-6597
authors.initials: UR
authors.lastname: Desai
mesh_terms: D055808:Drug Discovery; D005965:Glucuronates / Q000737:chemistry / Q000494:pharmacology*; D015844:Heparin Cofactor II / Q000819:agonists* / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005965:Glucuronates; D015844:Heparin Cofactor II; D006497:Heparan Sulfate; D054852:Small Molecule Libraries; C046100:glucuronic acid 2-sulfate
keywords: carbohydrates; chemical biology; glycosaminoglycans; in silico screening; serpins