Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model

Martin, Laure; Hamza, Hazem; Koch-Heier, Julia; Quernheim, Martin; Müller, Christin; Schreiber, André; Müller, Gerhard; Pleschka, Stephan; Ludwig, Stephan; Planz, Oliver

doi:10.1016/j.antiviral.2020.104806

Cited by 25 publications

(31 citation statements)

References 45 publications

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“…The RAF/MEK/ERK-signaling cascade is known to be a central pathway involved in virus replication of several RNA viruses, including influenza, RSV and coronavirus (109)(110)(111)(112). Previous studies using the MEK inhibitor ATR-002 demonstrated reduced influenza viral titers by preventing export of viral ribonucleoprotein complexes during the viral infection cycle (109,113). Moreover, there are indications that treatment with ATR-002 reduced cytokine expression, such as TNF-a, IL-1b, and IP-10 in vitro and in vivo and thereby could help to counteract or rebalance the SARS-CoV-2 induced hyperactivation of the immune response (114).…”

Section: Mek Inhibitor Atr-002mentioning

confidence: 99%

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

et al. 2021

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Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2nd Aug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.

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Section: Mek Inhibitor Atr-002mentioning

confidence: 99%

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

et al. 2021

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“…Viral spike protein and nucleocapsid proteins have been reported to stimulate the phosphorylation of ERK/MEK that triggers the release of various pro-inflammatory cytokines leading to ARDs and cytokine storm [62]. ATR-002 is a small molecule and inhibitor of Raf/MEK/ERK pathway [63]. Apart from the preclinical evidences, the outcome of the Phase I clinical trial showed the safety and clinical efficacy of ATR-002 in terms of reduced virulence and c ytokine storm (NCT04385420) [63].…”

Section: Mek Inhibitorsmentioning

confidence: 99%

“…ATR-002 is a small molecule and inhibitor of Raf/MEK/ERK pathway [63]. Apart from the preclinical evidences, the outcome of the Phase I clinical trial showed the safety and clinical efficacy of ATR-002 in terms of reduced virulence and c ytokine storm (NCT04385420) [63]. Further, In Vitro study using ACE2-A549 has shown p38 MAPKs activation in response to COVID-19 infection and blockage of p38 MAPK pathway by its inhibitor 'SB203580' showed a significant reduction in the level of IL-6, TNF-α and other inflammatory cytokines [49].…”

Section: Mek Inhibitorsmentioning

confidence: 99%

Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs

et al. 2021

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Coronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.

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“…Other research on the anti-influenza A virus showed three compounds with antiviral activity related to the efficacy of Flos Trollii and antiviral activities of compounds isolated from Pinus densiflora (pine tree) in cell culture [13,14]. Recent research demonstrated the antiviral activity of ATR-002 and selenium supplementation against influenza A virus in the cell culture [15,16]. Also, Yejin Jang and his teammates showed that lambda-carrageenan (λ-CGN) could be a promising and preventive agent for several respiratory infections, especially influenza A virus and SARS-CoV-2 [17].…”

Section: D Cell Culture Application For Sars-cov Mers-cov H1n1 and Sars-cov-2mentioning

confidence: 99%

Application of Cell Culture Models in Studying Viral Diseases (SARS, H1N1 Flu, MERS, COVID-19): A Review

Alavi¹,

Tajvar²,

Hadjizadeh³

2021

JICOA

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The emergence of recent viral outbreaks, especially the COVID-19 pandemic, and the resulting global mortality and damage has created an urgent need to accelerate the identification, prevention, and treatment of these viral diseases. Due to the limitations in the use of humans, and animal models in terms of time, costs, metabolism differences and ethical issues, in vitro models have become essential in virology research. In the present review, we collected the application of several used cell culture models in studies on four pathogenic viruses - severe acute respiratory syndrome coronavirus (SARS-CoV), influenza A virus (H1N1), middle east respiratory syndrome coronavirus (MERS-CoV), and 2019 novel coronavirus (SARS-CoV-2). These models included, 2D and 3D cell culture (organoids, microfluidic-chips, and bioprinted models). A collection of existing research on these viruses can help fight against the SARS-CoV-2 virus and speed it up against future emerging viruses. Moreover, it can show the shortcomings of in vitro models in virology studies that have been performed to date and provide researchers with new ideas for developing models that are more efficient to deal with similar viral outbreaks.

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Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model

Cited by 25 publications

References 45 publications

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs

Application of Cell Culture Models in Studying Viral Diseases (SARS, H1N1 Flu, MERS, COVID-19): A Review

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