Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection

Echavarría-Consuegra, Liliana; Cook, G. M. W.; Busnadiego, Idoia; Lefèvre, Charlotte; Keep, Sarah; Brown, Katherine A.; Doyle, Nicole; Dowgier, Giulia; Franaszek, Krzysztof; Moore, Nathan; Siddell, Stuart G.; Bickerton, Erica; Hale, Benjamin G.; Firth, Andrew E.; Brierley, Ian; Irigoyen, Nerea

doi:10.1371/journal.ppat.1009644

Cited by 70 publications

(86 citation statements)

References 121 publications

(209 reference statements)

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“…The contribution of ORF8 to ER stress was additionally confirmed by studying two genotypes of SARS-CoV-2, namely ORF8L and ORF8S, which carry a Leucine or a Serine at position 84 and were identified during the early stages of the pandemic in China. Despite lacking the aggregation motif found in SARS-CoV (270), both ORF8L and ORF8S are able to trigger the activation of ATF6 and IRE1 (71) and PERK (271). SARS-CoV-2 ORF8 is encoded by a hypervariable gene and several different polymorphisms have already been identified, as reported by a recent review (73).…”

Section: The Interaction Of Orf3a With the Apoptosis And Autophagy Pathwaysmentioning

confidence: 91%

SARS-CoV-2 and the Host Cell: A Tale of Interactions

Pizzato¹,

Baraldi²,

Sopetto³

et al. 2022

Front.Virol.

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The ability of a virus to spread between individuals, its replication capacity and the clinical course of the infection are macroscopic consequences of a multifaceted molecular interaction of viral components with the host cell. The heavy impact of COVID-19 on the world population, economics and sanitary systems calls for therapeutic and prophylactic solutions that require a deep characterization of the interactions occurring between virus and host cells. Unveiling how SARS-CoV-2 engages with host factors throughout its life cycle is therefore fundamental to understand the pathogenic mechanisms underlying the viral infection and to design antiviral therapies and prophylactic strategies. Two years into the SARS-CoV-2 pandemic, this review provides an overview of the interplay between SARS-CoV-2 and the host cell, with focus on the machinery and compartments pivotal for virus replication and the antiviral cellular response. Starting with the interaction with the cell surface, following the virus replicative cycle through the characterization of the entry pathways, the survival and replication in the cytoplasm, to the mechanisms of egress from the infected cell, this review unravels the complex network of interactions between SARS-CoV-2 and the host cell, highlighting the knowledge that has the potential to set the basis for the development of innovative antiviral strategies.

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Section: The Interaction Of Orf3a With the Apoptosis And Autophagy Pathwaysmentioning

confidence: 91%

SARS-CoV-2 and the Host Cell: A Tale of Interactions

Pizzato¹,

Baraldi²,

Sopetto³

et al. 2022

Front.Virol.

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“…All three branches of the UPR were induced in MHV, SARS-CoV-2, PEDV, and TGEV infected cells (Versteeg et al, 2007;Xue et al, 2018;Chen et al, 2021;Echavarria-Consuegra et al, 2021). Pharmacological inhibition of the UPR greatly regulated coronavirus replication, revealing the importance of this pathway for successful coronavirus replication.…”

Section: Regulation Of Coronavirus Replication By Unfolded Protein Responsementioning

confidence: 98%

“…Interestingly, the accessory protein 3a of SARS-CoV, a small multipass transmembrane protein, also activates the ATF4 and Chop promoter activities and thus may potentially also activate the PERK branch of UPR (Minakshi et al, 2009). MHV infection leads to activation of PERK-eIF2α-ATF4 branch (Figure 2; Echavarria-Consuegra et al, 2021).…”

Section: The Perk Signalingmentioning

confidence: 99%

“…It is well documented that coronavirus replication causes ER stress and induces UPR in the infected cells. Coronaviruses, such as SARS-CoV-2, SARS-CoV, mouse hepatitis virus (MHV), IBV, TGEV, and PEDV, can all induce significant ER stress following infection (Versteeg et al, 2007;Krahling et al, 2009;DeDiego et al, 2011;Liao et al, 2013;Xue et al, 2018;Echavarria-Consuegra et al, 2021). GRP78 and GRP94 are overexpressed in SARS-CoV infected cells.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

Xue

Feng

2021

Front. Microbiol.

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Coronavirus is an important pathogen with a wide spectrum of infection and potential threats to humans and animals. Its replication occurs in the cytoplasm and is closely related to the endoplasmic reticulum (ER). Studies reported that coronavirus infection causes ER stress, and cells simultaneously initiate unfolded protein response (UPR) to alleviate the disturbance of ER homeostasis. Activation of the three branches of UPR (PERK, IRE1, and ATF6) modulates various signaling pathways, such as innate immune response, microRNA, autophagy, and apoptosis. Therefore, a comprehensive understanding of the relationship between coronavirus and ER stress is helpful to understand the replication and pathogenesis of coronavirus. This paper summarizes the current knowledge of the complex interplay between coronavirus and UPR branches, focuses on the effect of ER stress on coronavirus replication and coronavirus resistance to host innate immunity, and summarizes possible drug targets to regulate the impact of coronavirus infection.

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“…the inositol requiring enzyme 1 (IRE1), the double stranded RNAactivated PK-like ER kinase (PERK), and the activating transcription factor 6 (ATF6) (Wang et al, 2014b). Although UPR activation is observed during SARS-CoV-2 infection (Echavarría-Consuegra et al, 2021), chemical activation of UPR by thapsigargin has been shown to inhibit coronavirus replication, including SARS-CoV-2 (Shaban et al, 2021). Furthermore, modulating the PERK-eIF2α pathway can inhibit the replication of the transmissible gastroenteritis porcine coronavirus (Xue et al, 2018).…”

Section: Streptococcus Pneumoniae -The Leading Cause Of Bacterial Pneumonia Worldwide -Andmentioning

confidence: 99%

Clofoctol inhibits SARS-CoV-2 replication and reduces lung pathology in mice

Belouzard

Machelart

Sencio

et al. 2021

Preprint

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The fastest way to implement a treatment against a new rapidly emerging viral disease consists in screening the potential antiviral activity of drugs approved for human use. This has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to its favorable safety profile and its pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC95 measured against SARS-CoV-2 in human pulmonary cells. Mechanistically, this compound inhibits SARS-CoV-2 at a post-entry step by specifically blocking translation initiation of viral RNA. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and improved pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients.

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Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection

Cited by 70 publications

References 121 publications

SARS-CoV-2 and the Host Cell: A Tale of Interactions

SARS-CoV-2 and the Host Cell: A Tale of Interactions

The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

Clofoctol inhibits SARS-CoV-2 replication and reduces lung pathology in mice

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