Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions

Kim, So Young; Jin, Weihua; Sood, Amika; Montgomery, David W.; Grant, Oliver C.; Fuster, Mark M.; Fu, Li; Dordick, Jonathan S.; Woods, Robert J.; Zhang, Fuming; Linhardt, Robert J.

doi:10.1016/j.antiviral.2020.104873

Cited by 278 publications

(421 citation statements)

References 50 publications

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“…Intriguingly, one of the candidates Tilorone was recently reported as an inhibitor of SARS-CoV-2 infection 27 . This coincidence, together with the recently reported interaction of SARS-CoV-2 Spike with the HS mimetic glycan heparin [28][29][30] and other evidence in support of a role for HS in the entry of SARS-CoV-2-related coronaviruses [22][23][24][25]31 prompted us to investigate the possibility of targeting HS as a COVID-19 therapeutic strategy.…”

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confidence: 80%

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Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro

Zhang

Chen

Swaroop

et al. 2020

Preprint

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Drugs capable of blocking the infectious cycle of the coronavirus SARS-CoV-2 are urgently needed to tackle the ongoing COVID-19 pandemic. To this end, the cell entry of SARS-CoV-2, initiated by the binding of the viral Spike (S) protein to human ACE2, has emerged as an attractive drug repurposing target. Here we use murine leukemia viruses pseudotyped with Spike from SARS-CoV or SARS-CoV-2 to demonstrate that ACE2-mediated coronavirus entry can be mitigated by heparin, a heparan sulfate-related glycan, or by genetic ablation of biosynthetic enzymes for the cell surface heparan sulfate proteoglycans (HSPGs). A drug repurposing screen targeting HSPG-dependent endocytosis identifies pharmacologically active endocytosis inhibitors that also abrogate coronavirus cell entry. Among them, Mitoxantrone (EC50=~10 nM) targets HSPGs directly, whereas Sunitinib and BNTX disrupt the actin network to impair HSPG-assisted viral entry. Gene expression profiling suggests potential combination regimens that optimally target HSPG-dependent viral entry. Altogether, our study establishes HSPGs as an assisting factor for ACE2 in endocytosis mediated coronavirus entry and identifies drugs that can be repurposed to target this important stage in the viral life cycle.

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confidence: 80%

“…How do HS glycans interact with Spike? Two recent studies posted at BioRxiv modeled the interactions of heparin with Spike using either full length Spike or just the RBD domain 29,44 .…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro

Zhang

Chen

Swaroop

et al. 2020

Preprint

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“…The mechanism of these interesting biosensors is based on the principle of sensing alterations with the dimensions of photons or light. Various kinds of optical biosensors that have been investigated for different viruses, especially human coronaviruses, are plasmon resonance (SPR) [ 114 ], ellipsometric and reflectometric interference spectroscopy (RIfS) [ 54 , 115 ], colorimetric [ 54 , 116 ], fluorescent [ 117 ], and surface-enhanced Raman scattering (SERS) [ 118 , 119 ]. Among these optical biosensing assays, SPR biosensors are of great importance as they can directly measure the alterations happening in the refractive index of light on the sensor surface, reflecting the analyte concentration.…”

Section: Detection Methodsmentioning

confidence: 99%

An Overview on SARS-CoV-2 (COVID-19) and Other Human Coronaviruses and Their Detection Capability via Amplification Assay, Chemical Sensing, Biosensing, Immunosensing, and Clinical Assays

et al. 2020

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A novel coronavirus of zoonotic origin (SARS-CoV-2) has recently been recognized in patients with acute respiratory disease. COVID-19 causative agent is structurally and genetically similar to SARS and bat SARS-like coronaviruses. The drastic increase in the number of coronavirus and its genome sequence have given us an unprecedented opportunity to perform bioinformatics and genomics analysis on this class of viruses. Clinical tests like PCR and ELISA for rapid detection of this virus are urgently needed for early identification of infected patients. However, these techniques are expensive and not readily available for point-of-care (POC) applications. Currently, lack of any rapid, available, and reliable POC detection method gives rise to the progression of COVID-19 as a horrible global problem. To solve the negative features of clinical investigation, we provide a brief introduction of the general features of coronaviruses and describe various amplification assays, sensing, biosensing, immunosensing, and aptasensing for the determination of various groups of coronaviruses applied as a template for the detection of SARS-CoV-2. All sensing and biosensing techniques developed for the determination of various classes of coronaviruses are useful to recognize the newly immerged coronavirus, i.e., SARS-CoV-2. Also, the introduction of sensing and biosensing methods sheds light on the way of designing a proper screening system to detect the virus at the early stage of infection to tranquilize the speed and vastity of spreading. Among other approaches investigated among molecular approaches and PCR or recognition of viral diseases, LAMP-based methods and LFAs are of great importance for their numerous benefits, which can be helpful to design a universal platform for detection of future emerging pathogenic viruses.

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“…Of these, severe acute respiratory syndrome coronavirus (SARS-CoV-2) (Lang et al, 2011), dengue (Chen et al, 1997), human papillomavirus (Giroglou et al, 2001), hepatitis B (Schulze et al, 2007), herpes simplex virus (Spear et al, 1992), human immunodeficiency virus (Connell and Lortat-Jacob, 2013), and others, target heparan sulfate (HS), a highly negatively charged linear polysaccharide present on the surface of all mammalian cells (Esko and Selleck, 2002). Infection by SARS-CoV-2, the causative agent of COVID-19, can be blocked with the HS derivative heparin (Kim et al, 2020;Mycroft-West et al, 2020;Clausen and Sandoval et al, 2020). SARS-CoV-2 attachment and infection requires binding to both HS and angiotensin converting enzyme 2 (ACE2) via distinct regions of the receptor binding domain (RBD) (Clausen and Sandoval et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

Martino

Kellman

Sandoval

et al. 2020

Preprint

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The human microbiota has a close relationship with human disease and it remodels components of the glycocalyx including heparan sulfate (HS). Studies of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike protein receptor binding domain suggest that infection requires binding to HS and angiotensin converting enzyme 2 (ACE2) in a codependent manner. Here, we show that commensal host bacterial communities can modify HS and thereby modulate SARS-CoV-2 spike protein binding and that these communities change with host age and sex. Common human-associated commensal bacteria whose genomes encode HS-modifying enzymes were identified. The prevalence of these bacteria and the expression of key microbial glycosidases in bronchoalveolar lavage fluid (BALF) was lower in adult COVID-19 patients than in healthy controls. The presence of HS-modifying bacteria decreased with age in two large survey datasets, FINRISK 2002 and American Gut, revealing one possible mechanism for the observed increase in COVID-19 susceptibility with age. In vitro, bacterial glycosidases from unpurified culture media supernatants fully blocked SARS-CoV-2 spike binding to human H1299 protein lung adenocarcinoma cells. HS-modifying bacteria in human microbial communities may regulate viral adhesion, and loss of these commensals could predispose individuals to infection. Understanding the impact of shifts in microbial community composition and bacterial lyases on SARS-CoV-2 infection may lead to new therapeutics and diagnosis of susceptibility.

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Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions

Cited by 278 publications

References 50 publications

Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro

Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro

An Overview on SARS-CoV-2 (COVID-19) and Other Human Coronaviruses and Their Detection Capability via Amplification Assay, Chemical Sensing, Biosensing, Immunosensing, and Clinical Assays

Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

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