Expression of 9-
            <i>O</i>
            - and 7,9-
            <i>O</i>
            -Acetyl Modified Sialic Acid in Cells and Their Effects on Influenza Viruses

Barnard, Karen N.; Wasik, Brian R.; LaClair, Justin R.; Buchholz, David W.; Weichert, Wendy S.; Alford-Lawrence, Brynn K.; Aguilar, Hector C.; Parrish, Colin R.

doi:10.1128/mbio.02490-19

Cited by 35 publications

(28 citation statements)

References 55 publications

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“…A key domain in the spike protein exhibits a high degree of morphological and sequence similarity to human Gal-3 ( Behloul et al, 2020 ). This NTD has been shown to bind Neu5Ac in vitro , an interaction that likely explains the high infectivity of SARS-CoV2 and may be essential for cell entry ( Alban et al, 2020 ; Barnard et al, 2019 ; Baker et al ., 2020 ). Inhibitors of Gal-3 that target regions of structural overlap with the NTD may possess dual binding capabilities, exhibiting a novel mechanism by which to inhibit viral entry ( Milanetti et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Modeling studies comparing the NTD of SARS-CoV2 and SARS-CoV have led to the same conclusion ( Behloul et al, 2020 ). The far greater abundance of Neu5Ac in the human body as compared to ACE2 receptors, particularly at common viral entry points such as the nasopharynx and oral mucosa, may explain the high transmissibility of SARS-CoV2 ( Barnard et al, 2019 ).…”

Section: Sars-cov2: Host Cell Attachment and Entrymentioning

confidence: 99%

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Immunopathology of galectin-3: an increasingly promising target in COVID-19

et al. 2020

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The pandemic brought on by the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has become a global health crisis, with over 22 million confirmed cases and 777,000 fatalities due to coronavirus disease 2019 (COVID-19) reported worldwide. The major cause of fatality in infected patients, now referred to as the “Cytokine Storm Syndrome” (CSS), is a direct result of aberrant immune activation following SARS-CoV2 infection and results in excess release of inflammatory cytokines, such as interleukin (IL)-1, tumor necrosis factor α (TNF-α), and IL-6, by macrophages, monocytes, and dendritic cells. Single cell analysis has also shown significantly elevated levels of galectin 3 (Gal-3) in macrophages, monocytes, and dendritic cells in patients with severe COVID-19 as compared to mild disease. Inhibition of Gal-3 reduces the release of IL-1, IL-6, and TNF-α from macrophages in vitro, and as such may hold promise in reducing the incidence of CSS. In addition, Gal-3 inhibition shows promise in reducing transforming growth factor ß (TGF-ß) mediated pulmonary fibrosis, likely to be a major consequence in survivors of severe COVID-19. Finally, a key domain in the spike protein of SARS-CoV2 has been shown to bind N-acetylneuraminic acid (Neu5Ac), a process that may be essential to cell entry by the virus. This Neu5Ac-binding domain shares striking morphological, sequence, and functional similarities with human Gal-3. Here we provide an updated review of the literature linking Gal-3 to COVID-19 pathogenesis. Dually targeting galectins and the Neu5Ac-binding domain of SARS-CoV2 shows tentative promise in several stages of the disease: preventing viral entry, modulating the host immune response, and reducing the post-infectious incidence of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Sars-cov2: Host Cell Attachment and Entrymentioning

confidence: 99%

Immunopathology of galectin-3: an increasingly promising target in COVID-19

et al. 2020

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“…Specifically, members of this species known to infect humans such as human coronavirus OC43 and HKU1 are among the viruses that bind 9-O-Ac-Sia (Tortorici et al, 2019). In humans, sialic acids including 9-O-Ac-Sia are most present within the body at mucosal surfaces such as the nasopharynx, lungs, and gastrointestinal tract (Barnard et al, 2019).…”

Section: Galectins and The Sars-cov2 Spike Proteinmentioning

confidence: 99%

A potential role for Galectin-3 inhibitors in the treatment of COVID-19

Caniglia

Guda

Asuthkar

et al. 2020

PeerJ

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The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the causative agent of coronavirus disease 2019 (COVID-19), has been declared a global pandemic by the World Health Organization. With no standard of care for the treatment of COVID-19, there is an urgent need to identify therapies that may be effective in treatment. Recent evidence has implicated the development of cytokine release syndrome as the major cause of fatality in COVID-19 patients, with elevated levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) observed in patients. Galectin-3 (Gal-3) is an animal lectin that has been implicated in the disease process of a variety of inflammatory conditions. Inhibitors of the small molecule Gal-3 have been shown to reduce the levels of both IL-6 and TNF-α in vitro and have shown anti-inflammatory effects in vivo. Additionally, a key domain in the spike protein of β-coronaviridae, a genus which includes SARS-CoV2, is nearly identical in morphology to human Gal-3. These spike proteins are critical for the virus’ entry into host cells. Here we provide a systematic review of the available literature and an impetus for further research on the use of Gal-3 inhibitors in the treatment of COVID-19. Further, we propose a dual mechanism by which Gal-3 inhibition may be beneficial in the treatment of COVID-19, both suppressing the host inflammatory response and impeding viral attachment to host cells.

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“…HEF recognizes 9- O -acetyl SA for entry into cells, while the esterase domain removes 9- O -acetyl-groups and liberates the virus from mucus and mis-assembled virus aggregates after budding. The 9- O -Ac on cells prevents the NA activity and HA binding of the influenza A type virus [ 44 ].…”

Section: Relationship Between C4- O - and C9- mentioning

confidence: 99%

SARS-CoV-2 Evolutionary Adaptation toward Host Entry and Recognition of Receptor O-Acetyl Sialylation in Virus–Host Interaction

Kim

2020

IJMS

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The recently emerged SARS-CoV-2 is the cause of the global health crisis of the coronavirus disease 2019 (COVID-19) pandemic. No evidence is yet available for CoV infection into hosts upon zoonotic disease outbreak, although the CoV epidemy resembles influenza viruses, which use sialic acid (SA). Currently, information on SARS-CoV-2 and its receptors is limited. O-acetylated SAs interact with the lectin-like spike glycoprotein of SARS CoV-2 for the initial attachment of viruses to enter into the host cells. SARS-CoV-2 hemagglutinin-esterase (HE) acts as the classical glycan-binding lectin and receptor-degrading enzyme. Most β-CoVs recognize 9-O-acetyl-SAs but switched to recognizing the 4-O-acetyl-SA form during evolution of CoVs. Type I HE is specific for the 9-O-Ac-SAs and type II HE is specific for 4-O-Ac-SAs. The SA-binding shift proceeds through quasi-synchronous adaptations of the SA-recognition sites of the lectin and esterase domains. The molecular switching of HE acquisition of 4-O-acetyl binding from 9-O-acetyl SA binding is caused by protein–carbohydrate interaction (PCI) or lectin–carbohydrate interaction (LCI). The HE gene was transmitted to a β-CoV lineage A progenitor by horizontal gene transfer from a 9-O-Ac-SA–specific HEF, as in influenza virus C/D. HE acquisition, and expansion takes place by cross-species transmission over HE evolution. This reflects viral evolutionary adaptation to host SA-containing glycans. Therefore, CoV HE receptor switching precedes virus evolution driven by the SA-glycan diversity of the hosts. The PCI or LCI stereochemistry potentiates the SA–ligand switch by a simple conformational shift of the lectin and esterase domains. Therefore, examination of new emerging viruses can lead to better understanding of virus evolution toward transitional host tropism. A clear example of HE gene transfer is found in the BCoV HE, which prefers 7,9-di-O-Ac-SAs, which is also known to be a target of the bovine torovirus HE. A more exciting case of such a switching event occurs in the murine CoVs, with the example of the β-CoV lineage A type binding with two different subtypes of the typical 9-O-Ac-SA (type I) and the exclusive 4-O-Ac-SA (type II) attachment factors. The protein structure data for type II HE also imply the virus switching to binding 4-O acetyl SA from 9-O acetyl SA. Principles of the protein–glycan interaction and PCI stereochemistry potentiate the SA–ligand switch via simple conformational shifts of the lectin and esterase domains. Thus, our understanding of natural adaptation can be specified to how carbohydrate/glycan-recognizing proteins/molecules contribute to virus evolution toward host tropism. Under the current circumstances where reliable antiviral therapeutics or vaccination tools are lacking, several trials are underway to examine viral agents. As expected, structural and non-structural proteins of SARS-CoV-2 are currently being targeted for viral therapeutic designation and development. However, the modern global society needs SARS-CoV-2 preventive and therapeutic drugs for infected patients. In this review, the structure and sialobiology of SARS-CoV-2 are discussed in order to encourage and activate public research on glycan-specific interaction-based drug creation in the near future.

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Expression of 9- O - and 7,9- O -Acetyl Modified Sialic Acid in Cells and Their Effects on Influenza Viruses

Cited by 35 publications

References 55 publications

Immunopathology of galectin-3: an increasingly promising target in COVID-19

Immunopathology of galectin-3: an increasingly promising target in COVID-19

A potential role for Galectin-3 inhibitors in the treatment of COVID-19

SARS-CoV-2 Evolutionary Adaptation toward Host Entry and Recognition of Receptor O-Acetyl Sialylation in Virus–Host Interaction

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