The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms

Paiardi, Giulia; Richter, Stefan; Oreste, Pasqua; Urbinati, Chiara; Rusnati, Marco; Wade, Rebecca C.

doi:10.1016/j.jbc.2021.101507

Cited by 68 publications

(87 citation statements)

References 57 publications

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“…DX600 is a competitive peptide inhibitor of ACE2 that only modestly inhibits the cellular entry of SARS-CoV-2 (and -1), suggesting that ACE2’s enzymatic activity is not essential for viral endocytosis [ 25 , 32 , 33 ]. On the other hand, heparin reduces SARS-CoV-1 and -2 infection very efficiently by directly competing with viral binding to host HSPGs [ 22 , 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Hudák¹,

Veres²,

Letoha

et al. 2022

IJMS

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Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike’s molecular interactions with syndecan-4 also involve syndecan-4’s cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta’s cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant’s spread.

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Section: Resultsmentioning

confidence: 99%

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Hudák¹,

Veres²,

Letoha

et al. 2022

IJMS

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show abstract

“…Spike has also been shown to bind to ACE2 and heparin independently in vitro such that a ternary complex can be generated involving all three molecules [ 53 ]. Computational docking and molecular dynamics simulations have identified a putative heparin/HS binding domain on Spike, a long positively charged patch that overlaps the S1/S2 junction and extends throughout the RBD [ 53 , 57 ]. Electron microscopic analysis indicates that heparin enhances the open conformation of the RBD suggesting a model whereby Spike binding to HS facilitates Spike-ACE2 interactions through a variety of mechanisms [ 53 ].…”

Section: Heparan Sulfate Proteoglycans and Spike Interactionsmentioning

confidence: 99%

“…Indeed, using in silico docking approaches, Clausen et al [ 53 ] present evidence for electrostatic interactions between heparin and several basic residues within the RBD of wild-type Spike (R346, R355, K444, R466). In another molecular modeling study, potential interactions between heparin and several basic residues within the RBD and the S1/S2 site were also identified [ 57 ]. Consequently, the introduction of several basic residues within the RBD of Omicron Spike may potentially increase HS binding.…”

Section: The Evolution Of “Perfect” Spike Proteinmentioning

confidence: 99%

The Future of the COVID-19 Pandemic: How Good (or Bad) Can the SARS-CoV2 Spike Protein Get?

Nugent

2022

Cells

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Severe acute respiratory syndrome virus 2 (SARS-CoV2) has infected an estimated 400 million people world-wide, causing approximately 6 million deaths from severe coronavirus disease 2019 (COVID-19). The SARS-CoV2 Spike protein plays a critical role in viral attachment and entry into host cells. The recent emergence of highly transmissible variants of SARS-CoV2 has been linked to mutations in Spike. This review provides an overview of the structure and function of Spike and describes the factors that impact Spike’s ability to mediate viral infection as well as the potential limits to how good (or bad) Spike protein can become. Proposed here is a framework that considers the processes of Spike-mediated SARS-CoV2 attachment, dissociation, and cell entry where the role of Spike, from the standpoint of the virus, is to maximize cell entry with each viral-cell collision. Key parameters are identified that will be needed to develop models to identify mechanisms that new Spike variants might exploit to enhance viral transmission. In particular, the importance of considering secondary co-receptors for Spike, such as heparan sulfate proteoglycans is discussed. Accurate models of Spike-cell interactions could contribute to the development of new therapies in advance of the emergence of new highly transmissible SARS-CoV2 variants.

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“…The sulfated polysaccharides that have already been investigated as anti-SARS-CoV-2 agents include heparin, heparin derivatives and glycosaminoglycan analogs (9,10,27). These sulfated polysaccharides are likely to remain effective against emerging variants of concern (VOC) that partially evade vaccine-induced immune response due to differences in polysaccharide and antibody binding sites on SARS-CoV-2 spike glycoprotein (10) and the conserved nature of the polybasic furin cleavage site, one of the major sites of heparin interaction and activity (28).…”

Section: Introductionmentioning

confidence: 99%

Safety and Pharmacokinetics of Intranasally Administered Heparin

et al. 2022

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Purpose Intranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity. Methods Double-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 μg) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects. Results UFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements. No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 h, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 h. Conclusions UFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 h after dosing.

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The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms

Cited by 68 publications

References 57 publications

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

The Future of the COVID-19 Pandemic: How Good (or Bad) Can the SARS-CoV2 Spike Protein Get?

Safety and Pharmacokinetics of Intranasally Administered Heparin

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