The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses

Schreiber, André; Viemann, Dorothee; Schöning, Jennifer; Schloer, Sebastian; Zambrano, Angeles Mecate; Brunotte, Linda; Faist, Aileen; Schöfbänker, Michael; Hrincius, Eike R.; Hoffmann, Helen; Hoffmann, Markus; Pöhlmann, Stefan; Rescher, Ursula; Planz, Oliver; Ludwig, Stephan

doi:10.1007/s00018-021-04085-1

Cited by 43 publications

(55 citation statements)

References 46 publications

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“…Because MEK inhibition leads to modulation rather than full suppression of the immune response 47,48 , zapnometinib might also be effective against post-COVID syndromes associated with SARS-CoV-2 infection. In line with our previous studies 24 , our results presented here underline the value of zapnometinib alone or in combination with other drugs that act at different stages of viral infection and disease progression, which could be the best possible strategy for controlling the disease and might be an important step forward in the current COVID-19 pandemic. On top of that, zapnometinib may still have other implications in infectious diseases.…”

Section: Discussionsupporting

confidence: 91%

“…Since both drugs lead to inhibition of NF-κB, an influence on type I IFN can be assumed since NF-κB is a major regulator of the IFN-beta enhanceosome 46 . In contrast to the NF-κB cascade, interfering with the Raf/MEK/ERK signaling pathway will not dampen type I IFNs and downstream IFN regulated genes as shown in this report and in our previous work 24 .…”

Section: Discussionsupporting

confidence: 59%

“…In our recent publication we demonstrated the antiviral efficacy of zapnometinib against various SARS-CoV-2 strains in cell culture 24 . Here, this in vitro analysis of the antiviral efficacy of zapnometinib against SARS-CoV-2 (BavPat1 and the alpha and beta variants) was extended to other highly pathogenic human coronaviruses (MERS-CoV and SARS-CoV-1) and evaluated using a Virospot reduction assay.…”

Section: Zapnometinib Inhibits Various Coronaviruses In Vitromentioning

confidence: 95%

“…This prompted us to analyze whether inhibition of the pathway would also lead to inhibition of SARS-CoV-2 replication. Indeed we could show that zapnometinib (ATR-002, PD 0184264), an oral MEK inhibitor, not only demonstrated antiviral activity against influenza virus 22,23 but also against SARS-CoV-2 in vitro 24 . Interestingly, the inhibitor also led to the reduction of expression of some virus-induced cytokines in infected cells 24 , although the relevance of this observation has still to be examined in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed we could show that zapnometinib (ATR-002, PD 0184264), an oral MEK inhibitor, not only demonstrated antiviral activity against influenza virus 22,23 but also against SARS-CoV-2 in vitro 24 . Interestingly, the inhibitor also led to the reduction of expression of some virus-induced cytokines in infected cells 24 , although the relevance of this observation has still to be examined in vivo. Additionally, zapnometinib showed no toxicity and was well tolerated in humans in a phase 1 study in healthy volunteers (NCT04385420).…”

Section: Introductionmentioning

confidence: 99%

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In vivo antiviral efficacy and immune dampening effect of zapnometinib emphasize a dual therapeutic potential against COVID-19

Füll¹,

Waidele²,

Hamza³

et al. 2022

Preprint

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Coronaviruses, in particular the current pandemic strains of SARS-CoV-2, represent an ever-evolving threat to human life. Currently available antiviral drugs are not suitable for severely infected patients in later hyperinflammatory stages of the disease. New therapeutics that inhibit virus propagation and target inflammation would be ideal. We demonstrate that the host targeted MEK inhibitor zapnometinib displays such a dual effect. The drug efficiently reduced virus titers of different SARS-CoV-2 variants and other highly pathogenic human coronaviruses such as SARS-CoV-1 and MERS-CoV in vitro. In a Syrian hamster infection model, zapnometinib reduced SARS-CoV-2 viral load and alleviated lung pathology. Drug safety biomarkers, body weight change and clinical observations, indicated that zapnometinib was well tolerated and showed no toxicity. Moreover, the immune dampening effect could be confirmed in an acute lung injury mouse model and in vitro experiments in primary human blood cells that demonstrated the reduction of disease related cytokines and chemokines. Thus, in contrast to direct-acting antivirals, zapnometinib displays a dual therapeutic effect highlighting its potential in the treatment of severe COVID-19 and other acute viral infections leading to hyperinflammation.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 59%

Section: Zapnometinib Inhibits Various Coronaviruses In Vitromentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In vivo antiviral efficacy and immune dampening effect of zapnometinib emphasize a dual therapeutic potential against COVID-19

Füll¹,

Waidele²,

Hamza³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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Inhibition of MEK signaling prevents SARS‐CoV2‐induced lung damage and improves the survival of infected mice

Xie

Klemsz

Kacena

et al. 2022

Journal of Medical Virology

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Coronavirus disease 2019 (COVID‐19) is the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Over 500 million confirmed cases of COVID‐19 have been recorded, with six million deaths. Thus, reducing the COVID‐19‐related medical burden is an unmet need. Despite a vaccine that is successful in preventing COVID‐19‐caused death, effective medication to relieve COVID‐19‐associated symptoms and alleviate disease progression is still in high demand. In particular, one in three COVID‐19 patients have signs of long COVID syndrome and are termed, long haulers. At present, there are no effective ways to treat long haulers. In this study, we determine the effectiveness of inhibiting mitogen‐activated protein kinase (MEK) signaling in preventing SARS‐CoV‐2‐induced lung damage in mice. We showed that phosphorylation of extracellular signal‐regulated kinase, a marker for MEK activation, is high in SARS‐CoV‐2‐infected lung tissues of mice and humans. We also showed that selumetinib, a specific inhibitor of the upstream MEK kinases, reduces cell proliferation, reduces lung damage following SARS‐CoV‐2 infection, and prolongs the survival of the infected mice. Selumetinib has been approved by the US Food and Drug Administration to treat cancer. Further analysis indicates that amphiregulin, an essential upstream molecule, was upregulated following SARS‐CoV‐2 infection. Our data suggest that MEK signaling activation represents a target for therapeutic intervention strategies against SARS‐CoV‐2‐induced lung damage and that selumetinib may be repurposed to treat COVID‐19.

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SARS‐CoV‐2, periodontal pathogens, and host factors: The trinity of oral post‐acute sequelae of COVID‐19

Schwartz,

Capistrano,

Gluck

et al. 2024

Reviews in Medical Virology

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COVID‐19 as a pan‐epidemic is waning but there it is imperative to understand virus interaction with oral tissues and oral inflammatory diseases. We review periodontal disease (PD), a common inflammatory oral disease, as a driver of COVID‐19 and oral post‐acute‐sequelae conditions (PASC). Oral PASC identifies with PD, loss of teeth, dysgeusia, xerostomia, sialolitis‐sialolith, and mucositis. We contend that PD‐associated oral microbial dysbiosis involving higher burden of periodontopathic bacteria provide an optimal microenvironment for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. These pathogens interact with oral epithelial cells activate molecular or biochemical pathways that promote viral adherence, entry, and persistence in the oral cavity. A repertoire of diverse molecules identifies this relationship including lipids, carbohydrates and enzymes. The S protein of SARS‐CoV‐2 binds to the ACE2 receptor and is activated by protease activity of host furin or TRMPSS2 that cleave S protein subunits to promote viral entry. However, PD pathogens provide additional enzymatic assistance mimicking furin and augment SARS‐CoV‐2 adherence by inducing viral entry receptors ACE2/TRMPSS, which are poorly expressed on oral epithelial cells. We discuss the mechanisms involving periodontopathogens and host factors that facilitate SARS‐CoV‐2 infection and immune resistance resulting in incomplete clearance and risk for ‘long‐haul’ oral health issues characterising PASC. Finally, we suggest potential diagnostic markers and treatment avenues to mitigate oral PASC.

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The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses

Cited by 43 publications

References 46 publications

In vivo antiviral efficacy and immune dampening effect of zapnometinib emphasize a dual therapeutic potential against COVID-19

In vivo antiviral efficacy and immune dampening effect of zapnometinib emphasize a dual therapeutic potential against COVID-19

Inhibition of MEK signaling prevents SARS‐CoV2‐induced lung damage and improves the survival of infected mice

SARS‐CoV‐2, periodontal pathogens, and host factors: The trinity of oral post‐acute sequelae of COVID‐19

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