| Download | - View final version: 7-Fluorosialyl glycosides are hydrolysis resistant but readily assembled by sialyltransferases providing easy access to more metabolically stable glycoproteins (PDF, 2.3 MiB)
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| DOI | Resolve DOI: https://doi.org/10.1021/acscentsci.0c01589 |
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| Author | Search for: Geissner, Andreas; Search for: Baumann, Lars; Search for: Morley, Thomas J.; Search for: Wong, Andrew K. O.; Search for: Sim, Lyann; Search for: Rich, Jamie R.; Search for: So, Pauline P. L.; Search for: Dullaghan, Edie M.; Search for: Lessard, Etienne1; Search for: Iqbal, Umar1; Search for: Moreno, Maria1; Search for: Wakarchuk, Warren W.; Search for: Withers, Stephen G.ORCID identifier: https://orcid.org/0000-0002-6722-5701 |
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| Affiliation | - National Research Council of Canada. Human Health Therapeutics
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| Format | Text, Article |
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| Subject | kinetic parameters; peptides and proteins; carbohydrates; hydrolysis; chemical biology |
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| Abstract | The maintenance of therapeutic glycoproteins within the circulatory system is associated, in large part, with the integrity of sialic acids as terminal sugars on the glycans. Glycoprotein desialylation, either by spontaneous cleavage or through host sialidases, leads to protein clearance, mainly through the liver. Thus, the installation of minimally modified sialic acids that are hydrolysis-resistant yet biologically equivalent should lead to increased circulatory half-lives and improved pharmacokinetic profiles. Here we describe the chemoenzymatic synthesis of CMP–sialic acid sugar donors bearing fluorine atoms at the 7-position, starting from the corresponding 4-deoxy-4-fluoro-N-acetylhexosamine precursors. For the derivative with natural stereochemistry we observe efficient glycosyl transfer by sialyltransferases, along with improved stability of the resultant 7-fluorosialosides toward spontaneous hydrolysis (3- to 5-fold) and toward cleavage by GH33 sialidases (40- to 250-fold). Taking advantage of the rapid transfer of 7-fluorosialic acid by sialyltransferases, we engineered the O-glycan of Interferon α-2b and the N-glycans of the therapeutic glycoprotein α1-antitrypsin. Studies of the uptake of the glyco-engineered α1-antitrypsin by HepG2 liver cells demonstrated the bioequivalence of 7-fluorosialic acid to sialic acid in suppressing interaction with liver cell lectins. In vivo pharmacokinetic studies reveal enhanced half-life of the protein decorated with 7-fluorosialic acid relative to unmodified sialic acid in the murine circulatory system. 7-Fluorosialylation therefore offers considerable promise as a means of prolonging circulatory half-lives of glycoproteins and may pave the way toward biobetters for therapeutic use. |
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| Publication date | 2021-01-18 |
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| Publisher | American Chemical Society |
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| Language | English |
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| Peer reviewed | Yes |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | 3944c4ec-76e2-4298-b29b-523a8254d643 |
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| Record created | 2021-04-12 |
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| Record modified | 2021-04-15 |
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