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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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DOI (Published version): 10.1021/acs.jmedchem.1c00794

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
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URI: https://cronfa.swan.ac.uk/Record/cronfa64860
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first_indexed 2023-11-17T18:33:54Z
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spelling v2 64860 2023-11-01 Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses a6b1181ebdbe42bd03b24cbdb559d082 0000-0002-5123-4937 Sumati Bhatia Sumati Bhatia true false 2023-11-01 CHEM 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. Journal Article Journal of Medicinal Chemistry 64 17 12774 12789 American Chemical Society (ACS) 0022-2623 1520-4804 Carbohydrates, Chemical biology, Genetics, Receptors, Viruses 9 9 2021 2021-09-09 10.1021/acs.jmedchem.1c00794 http://dx.doi.org/10.1021/acs.jmedchem.1c00794 COLLEGE NANME Chemistry COLLEGE CODE CHEM Swansea University 2024-01-02T11:31:37.6394361 2023-11-01T10:37:39.4811633 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Marlena N. Stadtmueller 1 Sumati Bhatia 0000-0002-5123-4937 2 Pallavi Kiran 3 Malte Hilsch 4 Valentin Reiter-Scherer 5 Lutz Adam 6 Badri Parshad 7 Matthias Budt 8 Simon Klenk 9 Katrin Sellrie 10 Daniel Lauster 11 Peter H. Seeberger 12 Christian P. R. Hackenberger 13 Andreas Herrmann 14 Rainer Haag 0000-0003-3840-162x 15 Thorsten Wolff 0000-0001-7688-236x 16
title Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses
spellingShingle Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses
Sumati Bhatia
title_short Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses
title_full Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses
title_fullStr Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses
title_full_unstemmed Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses
title_sort Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses
author_id_str_mv a6b1181ebdbe42bd03b24cbdb559d082
author_id_fullname_str_mv a6b1181ebdbe42bd03b24cbdb559d082_***_Sumati Bhatia
author Sumati Bhatia
author2 Marlena N. Stadtmueller
Sumati Bhatia
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
Thorsten Wolff
format Journal article
container_title Journal of Medicinal Chemistry
container_volume 64
container_issue 17
container_start_page 12774
publishDate 2021
institution Swansea University
issn 0022-2623
1520-4804
doi_str_mv 10.1021/acs.jmedchem.1c00794
publisher American Chemical Society (ACS)
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
url http://dx.doi.org/10.1021/acs.jmedchem.1c00794
document_store_str 0
active_str 0
description 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.
published_date 2021-09-09T11:31:39Z
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score 11.037056

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