A Hexasaccharide Containing Rare 2-O-Sulfate-Glucuronic Acid Residues Selectively Activates Heparin Cofactor II.

Autor: Sankarayanarayanan NV; Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA., Strebel TR; Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland., Boothello RS; Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA., Sheerin K; Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland., Raghuraman A; Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA., Sallas F; Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland., Mosier PD; Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA., Watermeyer ND; Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland., Oscarson S; Centre for Synthesis and Chemical Biology, University College of Dublin, Belfield, Dublin, 4, Ireland., Desai UR; Department of Medicinal Chemistry and Institute of Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2017 Feb 20; Vol. 56 (9), pp. 2312-2317. Date of Electronic Publication: 2017 Jan 26.
DOI: 10.1002/anie.201609541
Abstrakt: 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.
(© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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