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Heparin inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the surface protein (spike) S1 receptor binding domain with heparin

View ORCID ProfileCourtney J. Mycroft-West, View ORCID ProfileDunhao Su, View ORCID ProfileIsabel Pagani, View ORCID ProfileTimothy R. Rudd, View ORCID ProfileStefano Elli, View ORCID ProfileScott E. Guimond, View ORCID ProfileGavin Miller, View ORCID ProfileMaria C. Z. Meneghetti, View ORCID ProfileHelena B. Nader, View ORCID ProfileYong Li, View ORCID ProfileQuentin M. Nunes, Patricia Procter, View ORCID ProfileNicasio Mancini, View ORCID ProfileMassimo Clementi, View ORCID ProfileNicholas R. Forsyth, View ORCID ProfileJeremy E. Turnbull, View ORCID ProfileMarco Guerrini, View ORCID ProfileDavid G. Fernig, View ORCID ProfileElisa Vicenzi, View ORCID ProfileEdwin A. Yates, View ORCID ProfileMarcelo A. Lima, View ORCID ProfileMark A. Skidmore
doi: https://doi.org/10.1101/2020.04.28.066761
Courtney J. Mycroft-West
1Molecular & Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, ST5 5BG, UK
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Dunhao Su
2Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
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Isabel Pagani
3Viral Pathogens and Biosafety Unit, Division of Immunology, Transplantation and Disease, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
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Timothy R. Rudd
4National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, EN6 3QG, UK
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Stefano Elli
5Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133, Milan, Italy
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Scott E. Guimond
6School of Medicine, Keele University, Newcastle-Under-Lyme, Staffordshire, ST5 5BG, UK
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Gavin Miller
7School of Chemistry, Keele University, Newcastle-Under-Lyme, Staffordshire, ST5 5BG, UK
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Maria C. Z. Meneghetti
8Biochemistry Department, Federal University of São Paulo (UNIFESP), São Paulo, SP 04044-020 Brazil
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Helena B. Nader
8Biochemistry Department, Federal University of São Paulo (UNIFESP), São Paulo, SP 04044-020 Brazil
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Yong Li
2Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
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Quentin M. Nunes
9Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK
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Patricia Procter
1Molecular & Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, ST5 5BG, UK
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Nicasio Mancini
10Università Vita-Salute San Raffaele, Via Olgettina Milano, 58, 20132 Milan, Italy
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Massimo Clementi
10Università Vita-Salute San Raffaele, Via Olgettina Milano, 58, 20132 Milan, Italy
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Nicholas R. Forsyth
11Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Hartshill, Stoke-on-Trent, ST4 7QB
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Jeremy E. Turnbull
2Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
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Marco Guerrini
5Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133, Milan, Italy
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David G. Fernig
2Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
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Elisa Vicenzi
3Viral Pathogens and Biosafety Unit, Division of Immunology, Transplantation and Disease, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
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Edwin A. Yates
2Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
1Molecular & Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, ST5 5BG, UK
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Marcelo A. Lima
1Molecular & Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, ST5 5BG, UK
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Mark A. Skidmore
1Molecular & Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, ST5 5BG, UK
2Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK
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  • For correspondence: m.a.skidmore@keele.ac.uk
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Abstract

The dependence of the host on the interaction of hundreds of extracellular proteins with the cell surface glycosaminoglycan heparan sulphate (HS) for the regulation of homeostasis is exploited by many microbial pathogens as a means of adherence and invasion. The closely related polysac-charide heparin, the widely used anticoagulant drug, which is structurally similar to HS and is a common experimental proxy, can be expected to mimic the properties of HS. Heparin prevents infection by a range of viruses if added exogenously, including S-associated coronavirus strain HSR1 and here, we show that the addition of heparin (100 μg.ml-1) to vero cells inhibits invasion by SARS-CoV-2 by 70%. We also demonstrate that heparin binds to the Spike (S1) protein receptor binding domain and induces a conformational change, illustrated by surface plasmon resonance and circular dichroism spectroscopy studies. The structural features of heparin on which this interaction depends were investigated using a library of heparin derivatives and size-defined fragments. Binding is more strongly dependent on the presence of 2-O or 6-O sulphation, and the consequent conformational consequences in the heparin structure, than on N-sulphation. A hexasaccharide is required for conformational changes to be induced in the secondary structure that are comparable to those that arise from heparin binding. Enoxaparin, a low molecular weight clinical anticoagulant, also binds the S1 RBD protein and induces conformational change. These findings have implications for the rapid development of a first-line therapeutic by repurposing heparin as well as for next-generation, tailor-made, GAG-based antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.

Competing Interest Statement

The authors have declared no competing interest.

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Heparin inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the surface protein (spike) S1 receptor binding domain with heparin
Courtney J. Mycroft-West, Dunhao Su, Isabel Pagani, Timothy R. Rudd, Stefano Elli, Scott E. Guimond, Gavin Miller, Maria C. Z. Meneghetti, Helena B. Nader, Yong Li, Quentin M. Nunes, Patricia Procter, Nicasio Mancini, Massimo Clementi, Nicholas R. Forsyth, Jeremy E. Turnbull, Marco Guerrini, David G. Fernig, Elisa Vicenzi, Edwin A. Yates, Marcelo A. Lima, Mark A. Skidmore
bioRxiv 2020.04.28.066761; doi: https://doi.org/10.1101/2020.04.28.066761
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Heparin inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the surface protein (spike) S1 receptor binding domain with heparin
Courtney J. Mycroft-West, Dunhao Su, Isabel Pagani, Timothy R. Rudd, Stefano Elli, Scott E. Guimond, Gavin Miller, Maria C. Z. Meneghetti, Helena B. Nader, Yong Li, Quentin M. Nunes, Patricia Procter, Nicasio Mancini, Massimo Clementi, Nicholas R. Forsyth, Jeremy E. Turnbull, Marco Guerrini, David G. Fernig, Elisa Vicenzi, Edwin A. Yates, Marcelo A. Lima, Mark A. Skidmore
bioRxiv 2020.04.28.066761; doi: https://doi.org/10.1101/2020.04.28.066761

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