The Mechanistic Target of Rapamycin (mTOR): Novel Considerations as an Antiviral Treatment

Author(s): Kenneth Maiese*

Journal Name: Current Neurovascular Research

Volume 17 , Issue 3 , 2020

Become EABM
Become Reviewer
Call for Editor


Multiple viral pathogens can pose a significant health risk to individuals. As a recent example, the β-coronavirus family virion, SARS-CoV-2, has quickly evolved as a pandemic leading to coronavirus disease 2019 (COVID-19) and has been declared by the World Health Organization as a Public Health Emergency of International Concern. To date, no definitive treatment or vaccine application exists for COVID-19. Although new investigations seek to repurpose existing antiviral treatments for COVID-19, innovative treatment strategies not normally considered to have antiviral capabilities may be critical to address this global concern. One such avenue that may prove to be exceedingly fruitful and offer exciting potential as new antiviral therapy involves the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), and AMP activated protein kinase (AMPK). Recent work has shown that mTOR pathways in conjunction with AMPK may offer valuable targets to control cell injury, oxidative stress, mitochondrial dysfunction, and the onset of hyperinflammation, a significant disability associated with COVID-19. Furthermore, pathways that can activate mTOR may be necessary for anti-hepatitis C activity, reduction of influenza A virus replication, and vital for type-1 interferon responses with influenza vaccination. Yet, important considerations for the development of safe and effective antiviral therapy with mTOR pathways exist. Under some conditions, mTOR can act as a double edge sword and participate in virion replication and virion release from cells. Future work with mTOR as a potential antiviral target is highly warranted and with a greater understanding of this novel pathway, new treatments against several viral pathogens may successfully emerge.

Keywords: Akt, angiotensin converting enzyme 2, AMP activated protein kinase (AMPK), apoptosis, autophagy, cytokines, coronaviruses, COVID-19, diabetes mellitus, inflammation, influenza, interferons, interleukins, mechanistic target of rapamycin (mTOR), metformin, mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), oxidative stress, SARS-CoV-2, tumor necrosis factor-α, virion.

Borges do Nascimento IJ, Cacic N, Abdulazeem HM, et al. Novel Coronavirus infection (COVID-19) in humans: A scoping review and meta-analysis. J Clin Med 2020; 9(4): 941.
Zhou M, Zhang X, Qu J. Coronavirus disease 2019 (COVID-19): A clinical update. Front Med 2020; 2: 1-10.
Bayham J, Fenichel EP. 2020.
Sungnak W, Huang N, Becavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 2020; 26: 681-7.
McGonagle D, Sharif K, O’Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev 2020; 2020102537
Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 2020; 34(2): 1.
Fadini GP, Morieri ML, Longato E, Avogaro A. Prevalence and impact of diabetes among people infected with SARS-CoV-2. J Endocrinol Invest 2020; 2020: 1-3.
Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest 2020; 1138745
Amanat F, Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity 2020; 52(4): 583-9.
Fan HH, Wang LQ, Liu WL, et al. Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus (2019-nCoV) related coronavirus model. Chin Med J (Engl) 2020; 133(9): 1051-6.
Dorvash M, Farahmandnia M, Tavassoly I. a systems biology roadmap to decode mTOR control system in cancer. Interdiscip Sci 2020; 12(1): 1-11.
Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020; 13(1): 23-34.
Pan YR, Song JY, Fan B, et al. mTOR may interact with PARP-1 to regulate visible light-induced parthanatos in photoreceptors. Cell Commun Signal 2020; 18(1): 27.
Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci 2020; 10: 54.
Maiese K. Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. Br J Clin Pharmacol 2016; 82(5): 1245-66.
Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res 2016; 11(3): 372-85.
Maiese K, Chong ZZ, Shang YC, Wang S. mTOR: on target for novel therapeutic strategies in the nervous system. Trends Mol Med 2013; 19(1): 51-60.
Walters HE, Deneka-Hannemann S, Cox LS. Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging (Albany NY) 2016; 8(2): 231.
Maiese K. The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): Oversight for neurodegenerative disorders. Biochem Soc Trans 2018; 46(2): 351-60.
Huang D, Shen S, Cai M, et al. Role of mTOR complex in IGF-1 induced neural differentiation of DPSCs. J Mol Histol 2019; 50(3): 273-83.
Maiese K. Novel treatment strategies for the nervous system: circadian clock genes, non-coding RNAs, and forkhead transcription factors. Curr Neurovasc Res 2018; 15(1): 81-91.
Soltani A, Bahreyni A, Boroumand N, et al. Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proinflammatory diseases, current status and perspectives. J Cell Physiol 2017; 233(6): 4783-90.
Zimmerman MA, Biggers CD, Li PA. Rapamycin treatment increases hippocampal cell viability in an mTOR-independent manner during exposure to hypoxia mimetic, cobalt chloride. BMC Neurosci 2018; 19(1): 82.
Wang L, Lawrence JC Jr, Sturgill TW, Harris TE. Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J Biol Chem 2009; 284(22): 14693-7.
Beker MC, Caglayan B, Yalcin E, et al. Time-of-day dependent neuronal injury after ischemic stroke: Implication of circadian clock transcriptional factor bmal1 and survival kinase AKT. Mol Neurobiol 2018; 55(3): 2565-76.
Chong ZZ, Shang YC, Wang S, Maiese K. PRAS40 Is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection. PLoS One 2012; 7(9)e45456
Wang L, Harris TE, Lawrence JC Jr. Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J Biol Chem 2008; 283(23): 15619-27.
Shang YC, Chong ZZ, Wang S, Maiese K. WNT1 Inducible Signaling Pathway Protein 1 (WISP1) targets PRAS40 to govern beta-amyloid apoptotic injury of microglia. Curr Neurovasc Res 2012; 9(4): 239-49.
Wang H, Zhang Q, Wen Q, et al. Proline-rich Akt substrate of 40kDa (PRAS40): A novel downstream target of PI3k/Akt signaling pathway. Cell Signal 2012; 24(1): 17-24.
Gao D, Inuzuka H, Tan MK, et al. mTOR Drives Its Own Activation via SCF(betaTrCP)-Dependent Degradation of the mTOR Inhibitor DEPTOR. Mol Cell 2011; 44(2): 290-303.
Kim DH, Sarbassov DD, Ali SM, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003; 11(4): 895-904.
Maiese K. Impacting dementia and cognitive loss with innovative strategies: mechanistic target of rapamycin, clock genes, circular non-coding ribonucleic acids, and Rho/Rock. Neural Regen Res 2019; 14(5): 773-4.
Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6(11): 1122-8.
Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008; 416(3): 375-85.
Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J 2011; 436(1): 169-79.
Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006; 16(18): 1865-70.
An T, Zhang X, Li H, et al. GPR120 facilitates cholesterol efflux in macrophages through activation of AMPK signaling pathway. FEBS J 2020. [Epub ahead of print].
Maiese K. Moving to the rhythm with clock (circadian) genes, autophagy, mTOR, and SIRT1 in degenerative disease and cancer. Curr Neurovasc Res 2017; 14(3): 299-304.
Maiese K. Prospects and perspectives for WISP1 (CCN4) in Diabetes Mellitus. Curr Neurovasc Res 2020. [Epub ahead of print].
Pal PB, Sonowal H, Shukla K, Srivastava SK, Ramana KV. Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-alpha1/mTOR pathway. J Mol Endocrinol 2019; 63(1): 11-25.
Shokri Afra H, Zangooei M, Meshkani R, et al. Hesperetin is a potent bioactivator that activates SIRT1-AMPK signaling pathway in HepG2 cells. J Physiol Biochem 2019; 75(2): 125-33.
Zhao D, Sun X, Lv S, et al. Salidroside attenuates oxidized lowdensity lipoproteininduced endothelial cell injury via promotion of the AMPK/SIRT1 pathway. Int J Mol Med 2019; 43(6): 2279-90.
Kowalska M, Piekut T, Prendecki M, Sodel A, Kozubski W, Dorszewska J. Mitochondrial and nuclear DNA oxidative damage in physiological and pathological aging. DNA Cell Biol 2020. [Epub ahead of print].
Wu L, Xiong X, Wu X, et al. Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front Mol Neurosci 2020; 13: 28.
Wang N, Luo Z, Jin M, et al. Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina. Aging (Albany NY) 2019; 11(10): 3117-37.
Zhao Y, Wang Q, Wang Y, Li J, Lu G, Liu Z. Glutamine protects against oxidative stress injury through inhibiting the activation of PI3K/Akt signaling pathway in parkinsonian cell model. Environ Health Prev Med 2019; 24(1): 4.
Atef MM, El-Sayed NM, Ahmed AAM, Mostafa YM. Donepezil improves neuropathy through activation of AMPK signalling pathway in streptozotocin-induced diabetic mice. Biochem Pharmacol 2019; 159: 1-10.
Maiese K. New Insights for oxidative stress and Diabetes Mellitus. Oxid Med Cell Longev 2015; 2015875961
Maiese K. Harnessing the power of SIRT1 and non-coding RNAs in vascular disease. Curr Neurovasc Res 2017; 14(1): 82-8.
Peixoto CA, de Oliveira WH, da Rocha Araujo SM, Nunes AKS. 2017.
Sato T, Nakashima A, Guo L, Tamanoi F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem 2009; 284(19): 12783-91.
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115(5): 577-90.
Maiese K. WISP1: Clinical insights for a proliferative and restorative member of the CCN family. Curr Neurovasc Res 2014; 11(4): 378-89.
Gallyas F Jr, Sumegi B, Szabo C. Role of Akt activation in PARP inhibitor resistance in cancer. Cancers (Basel) 2020; 12(3): 532.
Chang H, Yuan W, Wu H, Yin X, Xuan H. Bioactive components and mechanisms of Chinese poplar propolis alleviates oxidized low-density lipoprotein-induced endothelial cells injury. BMC Complement Altern Med 2018; 18(1): 142.
Kamarudin MN, Mohd Raflee NA, Syed Hussein SS, Lo JY, Supriady H, Abdul Kadir H. (R)-(+)-alpha-Lipoic acid protected NG108-15 cells against H2O2-induced cell death through PI3K-Akt/GSK-3beta pathway and suppression of NF-kappabeta-cytokines. Drug Des Devel Ther 2014; 8: 1765-80.
Cheng P, Zuo X, Ren Y, et al. Adenosine A1-receptors modulate mtor signaling to regulate white matter inflammatory lesions induced by chronic cerebral hypoperfusion. Neurochem Res 2016; 41(12): 3272-7.
Jiang T, Yu JT, Zhu XC, et al. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol 2014; 171(13): 3146-57.
Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2016; 12(1): 1-222.
Maiese K, Chong ZZ, Shang YC, Wang S. Targeting disease through novel pathways of apoptosis and autophagy. Expert Opin Ther Targets 2012; 16(12): 1203-14.
Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010; 11(5): 390-401.
He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes 2013; 62(4): 1270-81.
Oda SS. Metformin protects against experimental acrylamide neuropathy in rats. Drug Dev Res 2017; 78(7): 349-59.
Hsia SH, Duran P, Lee ML, Davidson MB. Randomized controlled trial comparing hydroxychloroquine with pioglitazone as third-line agents in type 2 diabetic patients failing metformin plus a sulfonylurea: A pilot study. J Diabetes 2020; 12(1): 91-4.
Shives KD, Massey AR, May NA, Morrison TE, Beckham JD. 4EBP-dependent signaling supports west nile virus growth and protein expression. Viruses 2016; 8(10): 287.
Takeshita S, Ichikawa T, Taura N, et al. Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells. J Gastroenterol 2012; 47(2): 195-202.
Nandagopal N, Ali AK, Komal AK, Lee SH. The critical role of IL-15-PI3K-mTOR pathway in natural killer cell effector functions. Front Immunol 2014; 5: 187.
Seong RK, Kim JA, Shin OS. Wogonin, a flavonoid isolated from Scutellaria baicalensis, has anti-viral activities against influenza infection via modulation of AMPK pathways. Acta Virol 2018; 62(1): 78-85.
Saenwongsa W, Nithichanon A, Chittaganpitch M, et al. Metformin-induced suppression of IFN-alpha via mTORC1 signalling following seasonal vaccination is associated with impaired antibody responses in type 2 diabetes. Sci Rep 2020; 10(1): 3229.
Johri MK, Lashkari HV, Gupta D, Vedagiri D, Harshan KH. mTORC1 restricts hepatitis C virus RNA replication through ULK1-mediated suppression of miR-122 and facilitates post-replication events. J Gen Virol 2020; 101(1): 86-95.

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 28 September, 2020
Page: [332 - 337]
Pages: 6
DOI: 10.2174/1567202617666200425205122

Article Metrics

PDF: 121