The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

Carlos, Anthony J.; Ha, Dat P.; Yeh, Da‐Wei; Krieken, Richard Van; Tseng, Chun-Chih; Zhang, Pu; Gill, Parkash S.; Machida, Keigo; Lee, Amy

doi:10.1016/j.jbc.2021.100759

Cited by 117 publications

(146 citation statements)

References 34 publications

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“…In addition, patients with diabetes mellitus and COVID-19 exhibit increased ferritin levels (hyperferritinaemia), leading to altered iron homeostasis [ 27 , 28 , 29 ]. Further, endothelial damage and increased expression of endothelial receptors have been seen in COVID-19 patients [ 30 , 31 , 32 ]. Thus, the factors mentioned above, such as pre-existing endothelial damage and up-regulated endothelial receptors, glucocorticoid therapy, hyperglycaemia-associated complications such as hyperferritinaemia, and immune dysfunction of innate immune cells, are likely to contribute to the pathogenesis of CAM.…”

Section: Host and Iatrogenic Factors In The Pathogenesis Of Cammentioning

confidence: 99%

“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the Angiotensin-Converting Enzyme 2 (ACE2) receptor on endothelial cells, followed by the internalisation of viral particles leading to coagulation, endotheliitis and endothelial cell death [ 33 , 34 ]. Other than the ACE2 receptor, Glucose Regulated Protein 78 (GRP78) acts as a co-receptor for the recognition of SARS-CoV-2 spike protein and increases the internalisation of the virus ( Figure 1 A) [ 31 , 35 ]. GRP78 is a heat shock protein with a molecular weight of 78 kDa, also known as Heat Shock Protein A5 (HSPA5).…”

Section: Host and Iatrogenic Factors In The Pathogenesis Of Cammentioning

confidence: 99%

“…An increased serum GRP78 level has been noted in patients with COVID-19 infections compared to healthy controls [ 38 ]. Hence, the inhibition of the GRP78 receptor could reduce the internalisation of SARS-CoV-2 by reducing the expression of ACE2 receptors, further leading to reduced virus binding and infection severity [ 31 , 39 ]. Similar to the ACE2 receptor, GRP78 also mediates endothelial cell barrier disruption and inflammation [ 40 ].…”

Section: Host and Iatrogenic Factors In The Pathogenesis Of Cammentioning

confidence: 99%

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Connecting the Dots: Interplay of Pathogenic Mechanisms between COVID-19 Disease and Mucormycosis

Prakash

Skiada

Paul

et al. 2021

JoF

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Coronavirus disease (COVID-19)-associated mucormycosis (CAM) is an emerging threat globally, especially in India. More than 40,000 CAM cases have been reported in India. The emergence of CAM cases in India has been attributed to environmental, host, and iatrogenic factors. Mucorales spore burden has been reported globally; however, their presence is higher in tropical countries such as India, contributing to the emergence of CAM. Before the COVID-19 pandemic, patients with diabetes mellitus, haematological malignancies, solid organ transplants, corticosteroid therapy and neutropenia were more prone to mucormycosis, whereas in COVID-19 patients, virus-induced endothelial dysfunction, hyperglycaemia, and immune dysfunction following corticosteroid use increase the risk of acquiring mucormycosis. The interaction of Mucorales spores with the epithelial cells, followed by endothelial invasion, is a crucial step in the pathogenesis of mucormycosis. Endothelial damage and increased endothelial receptor expression induced by COVID-19 infection may predispose patients to CAM. COVID-19 infection may directly induce hyperglycaemia by damaging beta cells of the pancreas or by corticosteroid therapy, which may contribute to CAM pathogenesis. Iron acquisition from the host, especially in diabetic ketoacidosis (DKA) or deferoxamine therapy, is an important virulence trait of Mucorales. Similarly, the hyperferritinaemia caused by COVID-19 may act as a source of iron for Mucorales growth and invasion. In addition, corticosteroid treatment reduces or abolishes the innate immune functions of phagocytic cells contributing to the pathogenesis of CAM. This review aims to discuss primarily the host and iatrogenic factors shared between COVID-19 and mucormycosis that could explain the emergence of CAM.

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Section: Host and Iatrogenic Factors In The Pathogenesis Of Cammentioning

confidence: 99%

Section: Host and Iatrogenic Factors In The Pathogenesis Of Cammentioning

confidence: 99%

Section: Host and Iatrogenic Factors In The Pathogenesis Of Cammentioning

confidence: 99%

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Connecting the Dots: Interplay of Pathogenic Mechanisms between COVID-19 Disease and Mucormycosis

Prakash

Skiada

Paul

et al. 2021

JoF

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“…Notably, more recent studies indicate two other receptors involved in the SARS-CoV-2 attachment [ 8 ]: a transmembrane glycoprotein, CD147, localized on the surface of the host cell, and a chaperone heat shock protein, GRP78 [ 15 , 16 , 17 ]. Both could interact with several ligands as well as the RBD of the viral S protein, acting as multifunctional receptors for viral entry [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

More Is Always Better Than One: The N-Terminal Domain of the Spike Protein as Another Emerging Target for Hampering the SARS-CoV-2 Attachment to Host Cells

Gaetano

Capasso

Delre

et al. 2021

IJMS

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Although the approved vaccines are proving to be of utmost importance in containing the Coronavirus disease 2019 (COVID-19) threat, they will hardly be resolutive as new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, a single-stranded RNA virus) variants might be insensitive to the immune response they induce. In this scenario, developing an effective therapy is still a dire need. Different targets for therapeutic antibodies and diagnostics have been identified, among which the SARS-CoV-2 spike (S) glycoprotein, particularly its receptor-binding domain, has been defined as crucial. In this context, we aim to focus attention also on the role played by the S N-terminal domain (S1-NTD) in the virus attachment, already recognized as a valuable target for neutralizing antibodies, in particular, building on a cavity mapping indicating the presence of two druggable pockets and on the recent literature hypothesizing the presence of a ganglioside-binding domain. In this perspective, we aim at proposing S1-NTD as a putative target for designing small molecules hopefully able to hamper the SARS-CoV-2 attachment to host cells.

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“…It is a transmembrane glycoprotein composed of two subunits: the S1 subunit essential for binding to the host cell receptor and the S2 subunit responsible for the viral fusion to the host cell membrane (Laurini et al, 2020). The receptor-binding regions of the spike protein are capable of recognizing and attaching to multiple host receptors namely ACE2, GRP78, and NRP1 (Cantuti-Castelvetri et al, 2020;Carlos et al, 2021;Shang et al, 2020a). The elucidation of its structure and function makes it an attractive target for drug discovery and vaccine development.…”

Section: Introductionmentioning

confidence: 99%

Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein

Fernández

Quimque

Notarte

et al. 2021

Journal of Biomolecular Structure and Dynamics

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The severity of the COVID-19 pandemic has necessitated the search for drugs against SARS-CoV-2. In this study, we explored via in silico approaches myxobacterial secondary metabolites against various receptor-binding regions of SARS-CoV-2 spike which are responsible in recognition and attachment to host cell receptors mechanisms, namely ACE2, GRP78, and NRP1. In general, cyclic depsipeptide chondramides conferred high affinities toward the spike RBD, showing strong binding to the known viral hot spots Arg403, Gln493 and Gln498 and better selectivity compared to most host cell receptors studied. Among them, chondramide C3 (1) exhibited a binding energy which remained relatively constant when docked against most of the spike variants. Chondramide C (2) on the other hand exhibited strong affinity against spike variants identified in the United Kingdom (N501Y), South Africa (N501Y, E484K, K417N) and Brazil (N501Y, E484K, K417T). Chondramide C6 (9) showed highest BE towards GRP78 RBD. Molecular dynamics simulations were also performed for chondramides 1 and 2 against SARS-CoV-2 spike RBD of the Wuhan wild-type and the South African variant, respectively, where resulting complexes demonstrated dynamic stability within a 120-ns simulation time. Protein-protein binding experiments using HADDOCK illustrated weaker binding affinity for complexed chondramide ligands in the RBD against the studied host cell receptors. The chondramide derivatives in general possessed favorable pharmacokinetic properties, highlighting their potential as prototypic anti-COVID-19 drugs limiting viral attachment and possibly minimizing viral infection.

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The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

Cited by 117 publications

References 34 publications

Connecting the Dots: Interplay of Pathogenic Mechanisms between COVID-19 Disease and Mucormycosis

Connecting the Dots: Interplay of Pathogenic Mechanisms between COVID-19 Disease and Mucormycosis

More Is Always Better Than One: The N-Terminal Domain of the Spike Protein as Another Emerging Target for Hampering the SARS-CoV-2 Attachment to Host Cells

Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein

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