Evidence for Multiple Binding Modes in the Initial Contact Between SARS‐CoV‐2 Spike S1 Protein and Cell Surface Glycans**

Parafioriti, Michela; Ni, Minghong; Petitou, Maurice; Mycroft-West, Courtney J.; Rudd, Timothy R.; Gandhi, Neha S.; Ferro, Vito; Turnbull, Jeremy E.; Lima, Marcelo A.; Skidmore, Mark A.; Fernig, David G.; Yates, Edwin A.; Bisio, Antonella; Guerrini, Marco; Elli, Stefano

doi:10.1002/chem.202202599

Cited by 8 publications

(4 citation statements)

References 51 publications

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“…This suggests that movement of SARS-CoV-2 viral particles in a tissue, necessary to successfully infect a host, must depend on the ionic interactions of the Spike protein with host HS. In this instance, several binding modes for the Spike protein and HS have been proposed, Spike protein-HS interactions are multivalent in themselves and the virus particle possesses many Spike proteins, so is also multivalent at this level [62].…”

Section: Evidence For the Regulation Of Protein Transport By Hsmentioning

confidence: 99%

Interactions of proteins with heparan sulfate

Alotaibi,

Alsadun,

Alsaiari

et al. 2024

Essays in Biochemistry

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Heparan sulfate (HS) is a glycosaminoglycan, polysaccharides that are considered to have arisen in the last common unicellular ancestor of multicellular animals. In this light, the large interactome of HS and its myriad functions in relation to the regulation of cell communication are not surprising. The binding of proteins to HS determines their localisation and diffusion, essential for embryonic development and homeostasis. Following the biosynthesis of the initial heparosan polymer, the subsequent modifications comprise an established canonical pathway and a minor pathway. The more frequent former starts with N-deacetylation and N-sulfation of GlcNAc residues, the latter with C-5 epimerisation of a GlcA residue adjacent to a GlcNAc. The binding of proteins to HS is driven by ionic interactions. The multivalent effect arising from the many individual ionic bonds between a single protein and a polysaccharide chain results in a far stronger interaction than would be expected from an ion-exchange process. In many instances, upon binding, both parties undergo substantial conformational change, the resulting hydrogen and van der Waal bonds contributing significant free energy to the binding reaction. Nevertheless, ionic bonds dominate the protein–polysaccharide interaction kinetically. Together with the multivalent effect, this provides an explanation for the observed trapping of HS-binding proteins in extracellular matrix. Importantly, individual ionic bonds have been observed to be dynamic; breaking and reforming, while the protein remains bound to the polysaccharide. These considerations lead to a model for 1D diffusion of proteins in extracellular matrix on HS, involving mechanisms such as sliding, chain switching and rolling.

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Section: Evidence For the Regulation Of Protein Transport By Hsmentioning

confidence: 99%

Interactions of proteins with heparan sulfate

Alotaibi,

Alsadun,

Alsaiari

et al. 2024

Essays in Biochemistry

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“…Owing to their high negative charge, linear HS can dynamically bind to positively charged sites on the surface of various soluble proteins [25][26][27] and viruses [11,28]. Previous analyses of the Wuhan strain RBD surface revealed three putative heparin-binding sites [22,29]. Site I is defined by amino acid acids residues R346, N354, R355, K356, R357 and R466 [11], while sites II and III contain K424, R454, R457, K458, K462, R466, and R403, R408, K417, K444, respectively (Figure 1c).…”

Section: Molecular Modelling Of Voc S-protein Rbd Binding To Iagaia A...mentioning

confidence: 99%

Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility

Froese,

Mandalari,

Civera

et al. 2024

Preprint

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The heparan sulfate (HS)-rich extracellular matrix (ECM) serves as an initial interaction site for the homotrimeric spike (S)-protein of SARS-CoV-2 to facilitate subsequent docking to angiotensin-converting enzyme 2 (ACE2) receptors and cellular infection. Recent variants of concern (VOCs), notably Omicron, have evolved by swapping several amino acids to positively charged residues to enhance the S-protein trimer's interaction with the negatively charged HS polysaccharide chains in the matrix. These increased interactions, however, may reduce Omicron's ability to move through the HS-rich ECM to effectively find ACE2 receptors and infect cells, and raise the question of how HS-associated virus movement can be mechanistically explained. In this work, we show that Omicron S-proteins have evolved to balance HS interaction stability and dynamics, resulting in enhanced mobility on an HS-functionalized artificial matrix. Both properties are achieved by the ability of Omicrons S-proteins to cross-link at least two HS chains, providing both high avidity to retain the protein inside the HS-rich matrix, and fast dynamics, thus enabling direct S-protein switching between HS chains as a prerequisite for mobility at the cell surface. Optimized HS interactions can be targeted pharmaceutically, because an HS mimetic significantly suppressed surface binding and cellular infection specifically of the Omicron VOC. These findings suggest a robust way to interfere with SARS-CoV-2 Omicron infection and, potentially, future variants.

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“…It was rapidly determined that heparin was capable of inhibiting SARS-CoV-2 infection of cells by competing with HS for binding to the spike protein [ 10 ]. There is no evidence for selectivity for any HS structural motif [ 77 ], and indeed numerous different sulphated polymers have been shown to compete with HS binding to SARS-CoV-2 spike protein including marine sulphated glycans [ 78 , 79 ], pentosan polysulphate (a semi-synthetic sulphated xylan) [ 51 ] and others [ 80 ].…”

Section: Non-anticoagulant Action Of Heparin and Sepsismentioning

confidence: 99%

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Hogwood

Gray

2023

Pharmaceuticals

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Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms involved in sepsis such as pathogen interactions with the host cell and neutrophil recruitment and is a target for the pro-inflammatory enzyme heparanase. Heparin, a close structural relative of HS, is used in medicine as a powerful anticoagulant and antithrombotic. Many studies have shown that heparin can influence the course of sepsis-related processes as a result of its structural similarity to HS, including its strong negative charge. The anticoagulant activity of heparin, however, limits its potential in treatment of inflammatory conditions by introducing the risk of bleeding and other adverse side-effects. As the anticoagulant potency of heparin is largely determined by a single well-defined structural feature, it has been possible to develop heparin derivatives and mimetic compounds with reduced anticoagulant activity. Such heparin mimetics may have potential for use as therapeutic agents in the context of sepsis.

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Evidence for Multiple Binding Modes in the Initial Contact Between SARS‐CoV‐2 Spike S1 Protein and Cell Surface Glycans**

Cited by 8 publications

References 51 publications

Interactions of proteins with heparan sulfate

Interactions of proteins with heparan sulfate

Evolution of SARS-CoV-2 spike trimers towards optimized heparan sulfate cross-linking and inter-chain mobility

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

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