AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication

Rayner, Jonathan O.; Roberts, Rosemary A.; Kim, Jin; Poklepovic, Andrew; Roberts, Jeanette C.; Booth, Laurence; Dent, Paul

doi:10.1016/j.bcp.2020.114227

Cited by 42 publications

(58 citation statements)

References 32 publications

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“…2G ). Interestingly, a recent study showed GRP78 co-localizing with SARS-2-S following live virus infection and AR12, an inhibitor of chaperones including GRP78 suppressed SARS-CoV-2 infection (15). Collectively, these results suggest that through targeting host auxiliary chaperones such as GRP78 required for viral entry and production could offer a new strategy toward the development of broad spectrum anti-viral therapy.…”

Section: Resultsmentioning

confidence: 99%

GRP78 binds SARS-CoV-2 Spike protein and ACE2 and GRP78 depleting antibody blocks viral entry and infection in vitro

et al. 2021

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the current COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors may also play major roles in viral infection. Here we report that the stress-inducible molecular chaperone GRP78 can form a complex with the SARS-CoV-2 Spike protein and ACE2 intracellularly and on the cell surface, and that the substrate binding domain of GRP78 is critical for this function. Knock-down of GRP78 by siRNA dramatically reduced cell surface ACE2 expression. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159), selected for its ability to cause GRP78 endocytosis and its safe clinical profile in preclinical models, reduces cell surface ACE2 expression, SARS-CoV-2 Spike-driven viral entry, and significantly inhibits SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78.

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Section: Resultsmentioning

confidence: 99%

GRP78 binds SARS-CoV-2 Spike protein and ACE2 and GRP78 depleting antibody blocks viral entry and infection in vitro

et al. 2021

Preprint

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“…Nevertheless, the exact mechanisms underlying the role of autophagy in the emerging hCoV life cycle need further investigation. Some autophagy-based inhibitors demonstrate encouraging therapeutic potential against SARS-CoV-2 infections [ 50 , 53 ]. Therefore, repurposing of approved and well-tolerated drugs targeting autophagy would offer a welcome shortcut to rapidly develop treatments against COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, Bouhaddou et al recently reported that the pharmacological inhibitors of p38/MAPK signalling and PIKFYVE downstream of PIK3CA/AKT were found to possess strong antiviral efficacy in Vero E6 and A549-ACE2 cells infected with SARS-CoV-2 [ 48 ]. Rayner et al also demonstrated that AR12 (OSU-03012), a derivative of celecoxib, suppressed the production of infectious virions by enhancing autophagic flux in SARS-CoV-2 infected Vero cells [ 53 ]. Additionally, a recent preprint article from Gassen et al presented that autophagy activation can suppress viral propagation in SARS-CoV-2 infected NCI-H1299 and Vero FM cells by using the pro-autophagic compound spermidine and the AKT inhibitor MK-2206 [ 50 ].…”

Section: Coronavirus Infections and Autophagymentioning

confidence: 99%

“…Some autophagy based-drugs derived from FDA-approved drugs, compounds in clinical trials, or preclinical compounds were shown to be effective against SARS-CoV-2 in vitro [ 53 ]. Firstly, AR12 exhibited potent antiviral activity in SARS-CoV-2-infected Vero cells by increasing autophagic flux and enhancing virus protein degradation, which was associated with degradation of chaperone GRP78 [ 53 ]. This supported the re-entry of AR12 into the clinical therapeutic regimen of SARS-CoV-2 infection.…”

Section: Targeting Autophagy As a Promising Strategy For Covid-19mentioning

confidence: 99%

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The interplay between emerging human coronavirus infections and autophagy

Zhao

Mao

et al. 2021

Emerging Microbes & Infections

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Following outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2002 and 2012, respectively, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic emerging human coronavirus (hCoV). SARS-CoV-2 is currently causing the global coronavirus disease 2019 (COVID-19) pandemic. CoV infections in target cells may stimulate the formation of numerous double-membrane autophagosomes and induce autophagy. Several studies provided evidence that hCoV infections are closely related to various cellular aspects associated with autophagy. Autophagy may even promote hCoV infection and replication. However, so far it is unclear how hCoV infections induce autophagy and whether the autophagic machinery is necessary for viral propagation. Here, we summarize the most recent advances concerning the mutual interplay between the autophagic machinery and the three emerging hCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 and the model system mouse hepatitis virus. We also discuss the applicability of approved and well-tolerated drugs targeting autophagy as a potential treatment against COVID-19.

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“…Compound 26 decreases ACE2 and GRP78 expression in the cell surface and total GRP78 levels. Compound 26 not only catalytically inhibits the GRP78 ATPase activity but also reduces the chaperone proteins, which are linked with low S protein and the production of infectious virions ( Rayner et al, 2020 ).…”

Section: Targeting the S Proteinmentioning

confidence: 99%

An Overview of Spike Surface Glycoprotein in Severe Acute Respiratory Syndrome–Coronavirus

Kathiravan

Radhakrishnan

Namasivayam

et al. 2021

Front. Mol. Biosci.

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The novel coronavirus originated in December 2019 in Hubei, China. This contagious disease named as COVID-19 resulted in a massive expansion within 6 months by spreading to more than 213 countries. Despite the availability of antiviral drugs for the treatment of various viral infections, it was concluded by the WHO that there is no medicine to treat novel CoV, SARS-CoV-2. It has been confirmed that SARS-COV-2 is the most highly virulent human coronavirus and occupies the third position following SARS and MERS with the highest mortality rate. The genetic assembly of SARS-CoV-2 is segmented into structural and non-structural proteins, of which two-thirds of the viral genome encodes non-structural proteins and the remaining genome encodes structural proteins. The most predominant structural proteins that make up SARS-CoV-2 include spike surface glycoproteins (S), membrane proteins (M), envelope proteins (E), and nucleocapsid proteins (N). This review will focus on one of the four major structural proteins in the CoV assembly, the spike, which is involved in host cell recognition and the fusion process. The monomer disintegrates into S1 and S2 subunits with the S1 domain necessitating binding of the virus to its host cell receptor and the S2 domain mediating the viral fusion. On viral infection by the host, the S protein is further cleaved by the protease enzyme to two major subdomains S1/S2. Spike is proven to be an interesting target for developing vaccines and in particular, the RBD-single chain dimer has shown initial success. The availability of small molecules and peptidic inhibitors for host cell receptors is briefly discussed. The development of new molecules and therapeutic druggable targets for SARS-CoV-2 is of global importance. Attacking the virus employing multiple targets and strategies is the best way to inhibit the virus. This article will appeal to researchers in understanding the structural and biological aspects of the S protein in the field of drug design and discovery.

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AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication

Abstract: Graphical abstract

Cited by 42 publications

References 32 publications

GRP78 binds SARS-CoV-2 Spike protein and ACE2 and GRP78 depleting antibody blocks viral entry and infection in vitro

GRP78 binds SARS-CoV-2 Spike protein and ACE2 and GRP78 depleting antibody blocks viral entry and infection in vitro

The interplay between emerging human coronavirus infections and autophagy

An Overview of Spike Surface Glycoprotein in Severe Acute Respiratory Syndrome–Coronavirus

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