The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19

Basile, Maria Sofia; Cavalli, Eugenio; McCubrey, James A.; Hernández‐Bello, Jorge; Muñoz‐Valle, José Francisco; Fagone, Paolo; Nicoletti, Ferdinando

doi:10.1016/j.drudis.2021.11.002

Cited by 62 publications

(51 citation statements)

References 78 publications

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“…Furthermore, it has been shown that COVID-19 infected patient tissues and epithelial cells exhibit the abnormally activated mTOR signaling pathway, as evidenced by increased levels of phosphorylated 4E-BP1, AKT, S6K1 and mTOR (Appelberg et al, 2020;Mullen et al, 2021), suggesting the relevance of mTOR signaling activity and SARS-CoV-2 infection. More importantly, small molecule inhibitors targeting AKT and mTOR and engineered extracellular vesicles encapsulated microRNA targeting mTOR are able to significantly antagonize SARS-CoV-2 infection (Ibrahim et al, 2022), highlighting that inhibition of mTOR represents a feasible strategy for preventing COVID-19 (Basile et al, 2022).…”

Section: Mechanistic Target Of Rapamycin and Viral Skin Infectionmentioning

confidence: 99%

The regulation of skin homeostasis, repair and the pathogenesis of skin diseases by spatiotemporal activation of epidermal mTOR signaling

Wang

Cui

Chen

et al. 2022

Front. Cell Dev. Biol.

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The epidermis, the outmost layer of the skin, is a stratified squamous epithelium that protects the body from the external world. The epidermis and its appendages need constantly renew themselves and replace the damaged tissues caused by environmental assaults. The mechanistic target of rapamycin (mTOR) signaling is a central controller of cell growth and metabolism that plays a critical role in development, homeostasis and diseases. Recent findings suggest that mTOR signaling is activated in a spatiotemporal and context-dependent manner in the epidermis, coordinating diverse skin homeostatic processes. Dysregulation of mTOR signaling underlies the pathogenesis of skin diseases, including psoriasis and skin cancer. In this review, we discuss the role of epidermal mTOR signaling activity and function in skin, with a focus on skin barrier formation, hair regeneration, wound repair, as well as skin pathological disorders. We propose that fine-tuned control of mTOR signaling is essential for epidermal structural and functional integrity.

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Section: Mechanistic Target Of Rapamycin and Viral Skin Infectionmentioning

confidence: 99%

The regulation of skin homeostasis, repair and the pathogenesis of skin diseases by spatiotemporal activation of epidermal mTOR signaling

Wang

Cui

Chen

et al. 2022

Front. Cell Dev. Biol.

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“… A strong body of evidence demonstrates that viruses commonly commandeer host machinery required for viral replication, including activation of the PI3K/AKT/mTOR signaling pathway (reviewed in 51 ). For example, Mizutani et al demonstrated that infection of Vero E6 cells by coronavirus activates the AKT signaling pathway, 52 and that pAKT is essential for establishing persistent viral infection of these cells.…”

Section: Mechanism For the Antiviral Efficacy Of Opaganibmentioning

confidence: 99%

“… 56 Similarly, the AKT inhibitor MK-2206 suppressed viral replication, most likely by inducing autophagy. 54 , 57 Together, these results led to the proposal that inhibitors of the PI3K/AKT/mTOR signaling pathway may be effective for Covid-19 therapy; 51 , 58 however, none of the clinical trials assessing such drugs have reported positive data to date. 51 Beyond direct inhibition of viral replication, AKT inhibitors may attenuate excessive inflammation, cytokine storm, fibrosis, and thrombosis in Covid-19 patients.…”

Section: Mechanism For the Antiviral Efficacy Of Opaganibmentioning

confidence: 99%

“… 54 , 57 Together, these results led to the proposal that inhibitors of the PI3K/AKT/mTOR signaling pathway may be effective for Covid-19 therapy; 51 , 58 however, none of the clinical trials assessing such drugs have reported positive data to date. 51 Beyond direct inhibition of viral replication, AKT inhibitors may attenuate excessive inflammation, cytokine storm, fibrosis, and thrombosis in Covid-19 patients. 58 We and others have demonstrated that opaganib efficiently inhibits AKT phosphorylation in multiple cell types.…”

Section: Mechanism For the Antiviral Efficacy Of Opaganibmentioning

confidence: 99%

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Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Smith¹,

Maines²,

Keller³

et al. 2022

DDDT

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The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation. Opaganib (aka ABC294640) is a first-in-class clinical drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Recent work demonstrates that opaganib also has antiviral activity against several viruses including SARS-CoV-2. A recently completed multinational Phase 2/3 clinical trial of opaganib in patients hospitalized with Covid-19 demonstrated that opaganib can be safely administered to these patients, and more importantly, resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. Furthermore, acceleration of the clearance of the virus was observed in opaganib-treated patients. Understanding the biochemical mechanism for the anti-SARS-CoV-2 activity of opaganib is essential for optimizing Covid-19 treatment protocols. Opaganib inhibits three key enzymes in sphingolipid metabolism: sphingosine kinase-2 (SK2); dihydroceramide desaturase (DES1); and glucosylceramide synthase (GCS). Herein, we describe a tripartite model by which opaganib suppresses infection and replication of SARS-CoV-2 by inhibiting SK2, DES1 and GCS. The potential impact of modulation of sphingolipid signaling on multi-organ dysfunction in Covid-19 patients is also discussed.

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“…Another small molecule that has been found to regulate host translation is rapamycin, an oral drug that regulates kinases that are involved in host protein synthesis ( 197 , 205 , 206 ). eIF4E binding protein 1 (4E-BP1) and ribosomal protein p70 S6 kinase 1 (p70S6K1) are phosphorylated by mechanistic target of rapamycin complex 1 (mTORC1), which enhances cap-dependent protein translation ( 196 , 197 ). 4E1RCat is a dual inhibitor of the interaction of eIF4E: 4E-BP1 and eIF4E: eIF4G, which prevents the formation of the eIF4F complex and inhibits cap-dependent viral translation ( 10 ).…”

Section: Translational Strategies Against Sars-cov-2mentioning

confidence: 99%

Translational Control of COVID-19 and Its Therapeutic Implication

et al. 2022

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, which has broken out worldwide for more than two years. However, due to limited treatment, new cases of infection are still rising. Therefore, there is an urgent need to understand the basic molecular biology of SARS-CoV-2 to control this virus. SARS-CoV-2 replication and spread depend on the recruitment of host ribosomes to translate viral messenger RNA (mRNA). To ensure the translation of their own mRNAs, the SARS-CoV-2 has developed multiple strategies to globally inhibit the translation of host mRNAs and block the cellular innate immune response. This review provides a comprehensive picture of recent advancements in our understanding of the molecular basis and complexity of SARS-CoV-2 protein translation. Specifically, we summarize how this viral infection inhibits host mRNA translation to better utilize translation elements for translation of its own mRNA. Finally, we discuss the potential of translational components as targets for therapeutic interventions.

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The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19

Cited by 62 publications

References 78 publications

The regulation of skin homeostasis, repair and the pathogenesis of skin diseases by spatiotemporal activation of epidermal mTOR signaling

The regulation of skin homeostasis, repair and the pathogenesis of skin diseases by spatiotemporal activation of epidermal mTOR signaling

Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Translational Control of COVID-19 and Its Therapeutic Implication

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