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Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo

Sumati Bhatia Orcid Logo, Daniel Lauster, Markus Bardua, Kai Ludwig, Stefano Angioletti-Uberti, Nicole Popp, Ute Hoffmann, Florian Paulus, Matthias Budt, Marlena Stadtmüller, Thorsten Wolff, Alf Hamann, Christoph Böttcher, Andreas Herrmann, Rainer Haag

Biomaterials, Volume: 138, Pages: 22 - 34

Swansea University Author: Sumati Bhatia Orcid Logo

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Abstract

Inhibition of influenza A virus infection by multivalent sialic acid inhibitors preventing viral hemagglutinin binding to host cells of the respiratory tract is a promising strategy. However, optimal geometry and optimal ligand presentation on multivalent scaffolds for efficient inhibition both in v...

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Published in: Biomaterials
ISSN: 0142-9612
Published: Elsevier BV 2017
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URI: https://cronfa.swan.ac.uk/Record/cronfa64874
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spelling v2 64874 2023-11-01 Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo a6b1181ebdbe42bd03b24cbdb559d082 0000-0002-5123-4937 Sumati Bhatia Sumati Bhatia true false 2023-11-01 CHEM Inhibition of influenza A virus infection by multivalent sialic acid inhibitors preventing viral hemagglutinin binding to host cells of the respiratory tract is a promising strategy. However, optimal geometry and optimal ligand presentation on multivalent scaffolds for efficient inhibition both in vitro and in vivo application are still unclear. Here, by comparing linear and dendritic polyglycerol sialosides (LPGSA and dPGSA) we identified architectural requirements and optimal ligand densities for an efficient multivalent inhibitor of influenza virus A/X31/1 (H3N2). Due to its large volume, the LPGSA at optimal ligand density sterically shielded the virus significantly better than the dendritic analog. A statistical mechanics model rationalizes the relevance of ligand density, morphology, and the size of multivalent scaffolds for the potential to inhibit virus-cell binding. Optimized LPGSA inhibited virus infection at IC50 in the low nanomolar nanoparticle concentration range and also showed potent antiviral activity against two avian influenza strains A/Mallard/439/2004 (H3N2) and A/turkey/Italy/472/1999 (H7N1) post infection. In vivo application of inhibitors clearly confirmed the higher inhibition potential of linear multivalent scaffolds to prevent infection. The optimized LPGSA did not show any acute toxicity, and was much more potent than the neuraminidase inhibitor oseltamivir carboxylate in vivo. Combined application of the LPGSA and oseltamivir carboxylate revealed a synergistic inhibitory effect and successfully prevented influenza virus infection in mice. Journal Article Biomaterials 138 22 34 Elsevier BV 0142-9612 30 9 2017 2017-09-30 10.1016/j.biomaterials.2017.05.028 http://dx.doi.org/10.1016/j.biomaterials.2017.05.028 COLLEGE NANME Chemistry COLLEGE CODE CHEM Swansea University We are grateful for financial support within the SFB765 by the German Science Foundation (DFG) and the Focus Area Nanoscale of the Freie Universität Berlin. 2024-01-02T11:36:50.6383142 2023-11-01T10:41:54.6218518 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Sumati Bhatia 0000-0002-5123-4937 1 Daniel Lauster 2 Markus Bardua 3 Kai Ludwig 4 Stefano Angioletti-Uberti 5 Nicole Popp 6 Ute Hoffmann 7 Florian Paulus 8 Matthias Budt 9 Marlena Stadtmüller 10 Thorsten Wolff 11 Alf Hamann 12 Christoph Böttcher 13 Andreas Herrmann 14 Rainer Haag 15
title Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
spellingShingle Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
Sumati Bhatia
title_short Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
title_full Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
title_fullStr Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
title_full_unstemmed Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
title_sort Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo
author_id_str_mv a6b1181ebdbe42bd03b24cbdb559d082
author_id_fullname_str_mv a6b1181ebdbe42bd03b24cbdb559d082_***_Sumati Bhatia
author Sumati Bhatia
author2 Sumati Bhatia
Daniel Lauster
Markus Bardua
Kai Ludwig
Stefano Angioletti-Uberti
Nicole Popp
Ute Hoffmann
Florian Paulus
Matthias Budt
Marlena Stadtmüller
Thorsten Wolff
Alf Hamann
Christoph Böttcher
Andreas Herrmann
Rainer Haag
format Journal article
container_title Biomaterials
container_volume 138
container_start_page 22
publishDate 2017
institution Swansea University
issn 0142-9612
doi_str_mv 10.1016/j.biomaterials.2017.05.028
publisher Elsevier BV
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/10.1016/j.biomaterials.2017.05.028
document_store_str 0
active_str 0
description Inhibition of influenza A virus infection by multivalent sialic acid inhibitors preventing viral hemagglutinin binding to host cells of the respiratory tract is a promising strategy. However, optimal geometry and optimal ligand presentation on multivalent scaffolds for efficient inhibition both in vitro and in vivo application are still unclear. Here, by comparing linear and dendritic polyglycerol sialosides (LPGSA and dPGSA) we identified architectural requirements and optimal ligand densities for an efficient multivalent inhibitor of influenza virus A/X31/1 (H3N2). Due to its large volume, the LPGSA at optimal ligand density sterically shielded the virus significantly better than the dendritic analog. A statistical mechanics model rationalizes the relevance of ligand density, morphology, and the size of multivalent scaffolds for the potential to inhibit virus-cell binding. Optimized LPGSA inhibited virus infection at IC50 in the low nanomolar nanoparticle concentration range and also showed potent antiviral activity against two avian influenza strains A/Mallard/439/2004 (H3N2) and A/turkey/Italy/472/1999 (H7N1) post infection. In vivo application of inhibitors clearly confirmed the higher inhibition potential of linear multivalent scaffolds to prevent infection. The optimized LPGSA did not show any acute toxicity, and was much more potent than the neuraminidase inhibitor oseltamivir carboxylate in vivo. Combined application of the LPGSA and oseltamivir carboxylate revealed a synergistic inhibitory effect and successfully prevented influenza virus infection in mice.
published_date 2017-09-30T11:36:52Z
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