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A Hexasaccharide Containing Rare 2‐ O ‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II
Author(s) -
Sankaranarayanan Nehru Viji,
Strebel Tamara R.,
Boothello Rio S.,
Sheerin Kevin,
Raghuraman Arjun,
Sallas Florence,
Mosier Philip D.,
Watermeyer Nicholas D.,
Oscarson Stefan,
Desai Umesh R.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201609541
Subject(s) - serpin , glucuronic acid , heparin cofactor ii , heparan sulfate , biochemistry , chemistry , antithrombin , heparin , glycosaminoglycan , cofactor , chemical biology , enzyme , polysaccharide , gene
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.