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Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses

Marlena N. Stadtmueller, Sumati Bhatia Orcid Logo, Pallavi Kiran, Malte Hilsch, Valentin Reiter-Scherer, Lutz Adam, Badri Parshad, Matthias Budt, Simon Klenk, Katrin Sellrie, Daniel Lauster, Peter H. Seeberger, Christian P. R. Hackenberger, Andreas Herrmann, Rainer Haag Orcid Logo, Thorsten Wolff Orcid Logo

Journal of Medicinal Chemistry, Volume: 64, Issue: 17, Pages: 12774 - 12789

Swansea University Author: Sumati Bhatia Orcid Logo

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Abstract

The development of multivalent sialic acid-based inhibitors active against a variety of influenza A virus (IAV) strains has been hampered by high genetic and structural variability of the targeted viral hemagglutinin (HA). Here, we addressed this challenge by employing sialylated polyglycerols (PGs)...

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Published in: Journal of Medicinal Chemistry
ISSN: 0022-2623 1520-4804
Published: American Chemical Society (ACS) 2021
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa64860
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Abstract: The development of multivalent sialic acid-based inhibitors active against a variety of influenza A virus (IAV) strains has been hampered by high genetic and structural variability of the targeted viral hemagglutinin (HA). Here, we addressed this challenge by employing sialylated polyglycerols (PGs). Efficacy of prototypic PGs was restricted to a narrow spectrum of IAV strains. To understand this restriction, we selected IAV mutants resistant to a prototypic multivalent sialylated PG by serial passaging. Resistance mutations mapped to the receptor binding site of HA, which was accompanied by altered receptor binding profiles of mutant viruses as detected by glycan array analysis. Specifying the inhibitor functionalization to 2,6-α-sialyllactose (SL) and adjusting the linker yielded a rationally designed inhibitor covering an extended spectrum of inhibited IAV strains. These results highlight the importance of integrating virological data with chemical synthesis and structural data for the development of sialylated PGs toward broad anti-influenza compounds.
Keywords: Carbohydrates, Chemical biology, Genetics, Receptors, Viruses
College: Faculty of Science and Engineering
Issue: 17
Start Page: 12774
End Page: 12789