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  Evaluation of multivalent sialylated polyglycerols for resistance induction in and broad antiviral activity against influenza A viruses

Stadtmueller, M. N., Bhatia, S., Kiran, P., Hilsch, M., Reiter-Scherer, V., Adam, L., et al. (2021). Evaluation of multivalent sialylated polyglycerols for resistance induction in and broad antiviral activity against influenza A viruses. Journal of Medicinal Chemistry, 64(17), 12774-12789. doi:10.1021/acs.jmedchem.1c00794.

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Stadtmueller, Marlena N., Author
Bhatia, Sumati, Author
Kiran, Pallavi, Author
Hilsch, Malte, Author
Reiter-Scherer, Valentin, Author
Adam, Lutz, Author
Parshad, Badri, Author
Budt, Matthias, Author
Klenk, Simon, Author
Sellrie, Katrin1, Author           
Lauster, Daniel, Author
Seeberger, Peter H.2, Author           
Hackenberger, Christian P. R., Author
Herrmann, Andreas, Author
Haag, Rainer, Author
Wolff, Thorsten, Author
Affiliations:
1Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863286              
2Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863308              

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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.

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Language(s): eng - English
 Dates: 2021-08-252021
 Publication Status: Published in print
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 Identifiers: DOI: 10.1021/acs.jmedchem.1c00794
BibTex Citekey: doi:10.1021/acs.jmedchem.1c00794
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Title: Journal of Medicinal Chemistry
Source Genre: Journal
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Publ. Info: Washington DC : ACS Publications
Pages: - Volume / Issue: 64 (17) Sequence Number: - Start / End Page: 12774 - 12789 Identifier: ISSN: 0022-2623