Antiviral Potential of ERK/MAPK and PI3K/AKT/mTOR Signaling Modulation for Middle East Respiratory Syndrome Coronavirus Infection as Identified by Temporal Kinome Analysis

Kindrachuk, Jason; Ork, Britini L.; Hart, Brit J.; Mazur, Steven; Holbrook, Michael R.; Frieman, Matthew B.; Traynor, Dawn; Johnson, Reed F.; Dyall, Julie; Kuhn, Jens H.; Olinger, Gene G.; Hensley, Lisa E.; Jahrling, Peter B.

doi:10.1128/aac.03659-14

Cited by 361 publications

(419 citation statements)

References 46 publications

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“…W. Dong, et al Antiviral Research 173 (2020) 104651 2015; Kindrachuk et al, 2015;Lee et al, 2016;Mizutani et al, 2005). Nevertheless, no studies to date have focused on detecting global phosphorylation events in host cells during CoV infection.…”

Section: The Phosphorylation Involved In the Host Response To Tgev Inmentioning

confidence: 99%

“…Yang et al found that PEDV infection stimulated the activation of EGFR and its downstream STAT3 cascade, which increased viral infection by negatively regulating type I interferon (IFN-I) signaling (Yang et al, 2018). The ERK/MAPK and PI3K/AKT/mTOR signaling responses play important roles in MERS-CoV infection (Kindrachuk et al, 2015), and JNK and phosphatidylinositol 3′-kinase (PI3K)/Akt are required for establishing persistent SARS-CoV infection in Vero E6 cells (Mizutani et al, 2005). Our phosphoproteomic analysis found that TGEV infection enhanced (A and E) Effect of inhibitors on viral yields.…”

Section: P38 Is One Of the Targets For The Inhibitory Activity Of A9mentioning

confidence: 99%

“…RTKs are the primary mediators of many signals and control many downstream cascades, including phosphoinositide 3-kinase (PI3K), MAPK and Ca2 + pathways (Schlessinger, 2000). Several studies have shown that phosphoinositide 3-kinase (PI3K) signaling and STAT3 cascades, which are downstream of RTKs, play important roles in the life cycle of CoV (Hu et al, 2016;Kindrachuk et al, 2015;Mizutani et al, 2005;Yang et al, 2018). Further studies are required to explore whether these downstream cascades are involved in the inhibitory activity of A9 against TGEV replication.…”

Section: P38 Is One Of the Targets For The Inhibitory Activity Of A9mentioning

confidence: 99%

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Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways

et al. 2020

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Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, and no approved therapeutics are currently available. Here, A9, a receptor tyrosine kinase inhibitor (RTKI) of the tyrphostin class, is identified as a robust inhibitor of transmissible gastroenteritis virus (TGEV) infection in cell-based assays. Moreover, A9 exhibited potent antiviral activity against the replication of various CoVs, including murine hepatitis virus (MHV), porcine epidemic diarrhea virus (PEDV) and feline infectious peritonitis virus (FIPV). We further performed a comparative phosphoproteomic analysis to investigate the mechanism of action of A9 against TGEV infection in vitro. We specifically identified p38 and JNK1, which are the downstream molecules of receptor tyrosine kinases (RTKs) required for efficient TGEV replication, as A9 targets through plaque assays, qRT-PCR and Western blotting assays. p38 and JNK1 inhibitors and RNA interference further showed that the inhibitory activity of A9 against TGEV infection was mainly mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. All these findings indicated that the RTKI A9 directly inhibits TGEV replication and that its inhibitory activity against TGEV replication mainly occurs by targeting p38, which provides vital clues to the design of novel drugs against CoVs.

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Section: The Phosphorylation Involved In the Host Response To Tgev Inmentioning

confidence: 99%

Section: P38 Is One Of the Targets For The Inhibitory Activity Of A9mentioning

confidence: 99%

Section: P38 Is One Of the Targets For The Inhibitory Activity Of A9mentioning

confidence: 99%

See 1 more Smart Citation

Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways

et al. 2020

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“…Kinase-involved signaling pathways are widely involved in the regulation of cellular machineries of metabolism, transcription and translation for cell proliferation, differentiation, death, among others. Studies have shown that the ERK pathway and cyclin-dependent kinases (CDKs) are essential for the viral replication of CoV and IFV [5,85]. Targeting protein kinases or signaling pathways becomes a focus in the therapeutic development for broad-spectrum antiviral agents.…”

Section: Targeting Signaling Pathwaysmentioning

confidence: 99%

Repurposing host-based therapeutics to control coronavirus and influenza virus

Wang

2019

Drug Discovery Today

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Teaser This communication focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus.The development of highly effective antiviral agents has been a major objective in virology and pharmaceutics. Drug repositioning has emerged as a cost-effective and time-efficient alternative approach to traditional drug discovery and development. This new shift focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for the therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus. Host-based antiviral agents target host cellular machineries essential for viral infections or innate immune responses to interfere with viral pathogenesis. This review discusses current knowledge, prospective applications and challenges in the repurposing of clinically approved and preclinically studied drugs for newly indicated antiviral therapeutics.

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“…Interventions that could manipulate this hostpathogen relationship via modulation of the host response to MERS-CoV infection may help improve mortality rates in patients with MERS. 37 For instance, genome analysis suggest that immune signaling modulation may affect outcome, 38 and adenosine deaminase may prevent MERS-CoV entry into host cells. 39 A range of Host-Directed Therapies (HDTs) have the potential for improving the treatment outcomes of severe lung infections.…”

Section: Mers-cov Pathogenesis and Host Immune Responsesmentioning

confidence: 99%

Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections

Zumla

Azhar

Arabi

et al. 2015

International Journal of Infectious Diseases

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Three years after its first discovery in Jeddah Saudi Arabia, the novel zoonotic pathogen of humans, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) continues to be a major threat to global health security.(1) Sporadic community acquired cases of MERS continue to be reported from the Middle East. The recent nosocomial outbreaks in hospitals in Seoul, Korea and at the National Guard Hospital in Riyadh, Saudi Arabia indicate the epidemic potential of MERS-CoV. Currently there are no effective anti-MERS-CoV anti-viral agents or therapeutics and MERS is associated with a high mortality rate (40%) in hospitalised patients. A large proportion of MERS patients who die have a range of pulmonary pathology ranging from pneumonia to adult respiratory distress syndrome with multi-organ failure, compounded by co-morbidities, reflecting a precarious balance of interactions between the host-immune system and MERS-CoV. Whilst we wait for new MERS-CoV specific drugs, therapeutics and vaccines to be developed, there is a need to advance a range of Host-Directed Therapies. A range of HDTs are available, including commonly used drugs with good safety profiles, which could augment host innate and adaptive immune mechanisms to MERS-CoV, modulate excessive inflammation and reduce lung tissue destruction. We discuss the rationale and potential of using Host-Directed Therapies for improving the poor treatment outcomes associated with MERS. Carefully designed randomized controlled trials will be needed to determine whether HDTs could benefit patients with MERS. The recurrent outbreaks of MERS-CoV infections at hospitals in the Middle East present unique opportunities to conduct randomized clinical trials. The time has come for a more coordinated global response to MERS and a multidisciplinary global MERS-CoV response group is required to take forward priority research agendas.

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Antiviral Potential of ERK/MAPK and PI3K/AKT/mTOR Signaling Modulation for Middle East Respiratory Syndrome Coronavirus Infection as Identified by Temporal Kinome Analysis

Cited by 361 publications

References 46 publications

Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways

Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways

Repurposing host-based therapeutics to control coronavirus and influenza virus

Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections

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