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566. Evaluation of Multivalent Sialylated Polyglycerols for Resistance and Broad Antiviral Activity against Influenza Viruses

M. N. Stadtmueller, S. Bhatia, P. Kiran, M. Hilsch, V. Reiter-Scherer, L. Adam, B. Parshad, M. Budt, S. Klenk, K. Sellrie, D. Lauster, P. H. Seeberger, C. Hackenberger, A. Herrmann, R. Haag, T. Wolff – 2021

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.

Title
566. Evaluation of Multivalent Sialylated Polyglycerols for Resistance and Broad Antiviral Activity against Influenza Viruses
Author
M. N. Stadtmueller, S. Bhatia, P. Kiran, M. Hilsch, V. Reiter-Scherer, L. Adam, B. Parshad, M. Budt, S. Klenk, K. Sellrie, D. Lauster, P. H. Seeberger, C. Hackenberger, A. Herrmann, R. Haag, T. Wolff
Date
2021
Identifier
DOI: 10.1021/acs.jmedchem.1c00794
Source(s)
Citation
J. Med. Chem., 2021, 64, 17, 12774–12789
Type
Text