Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Can We Use mTOR Inhibitors for COVID-19 Therapy?

Author(s): Ina Y. Aneva *, Solomon Habtemariam, Maciej Banach, Parames C. Sil , Kasturi Sarkar, Adeleh Sahebnasagh , Mohammad Amjad Kamal, Maryam Khayatkashani and Hamid Reza Khayat Kashani*

Volume 25, Issue 11, 2022

Published on: 14 January, 2022

Page: [1805 - 1808] Pages: 4

DOI: 10.2174/1386207325666211130140923

Price: $65

Abstract

Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes acute inflammation due to extensive replication of the virus in the epithelial cells of the upper and lower respiratory system.

The mammalian target of rapamycin (mTOR) is a l signalling protein with critical functions in cell growth, metabolism, and proliferation. It is known for its regulatory functions in protein synthesis and angiogenesis cascades. The structure of mTOR consists of two distinct complexes (mTORC1 and mTORC2) with diverse functions at different levels of the signalling pathway. By activating mRNA translation, the mTORC1 plays a key role in regulating protein synthesis and cellular growth. On the other hand, the functions of mTORC2 are mainly associated with cell proliferation and survival.

By using an appropriate inhibitor at the right time, mTOR modulation could provide immunosuppressive opportunities as antirejection regimens in organ transplantation as well as in the treatment of autoimmune diseases and solid tumours. The mTOR also has an important role in the inflammatory process. Inhibitors of mTOR might indeed be promising agents in the treatment of viral infections. They have further been successfully used in patients with severe influenza A/H1N1 pneumonia and acute respiratory failure. The officially accepted mTOR inhibitors that have undergone clinical testing are sirolimus, everolimus, temsirolimus, and tacrolimus. Thus, further studies on mTOR inhibitors for SARS-CoV-2 infection or COVID-19 therapy are well merited.

Keywords: mTOR inhibitors, COVID-19, SARS-CoV-2, sirolimus, everolimus, temsirolimus, rapamycin.

Next »
[1]
Saxton, R.A.; Sabatini, D.M. mTOR signaling in growth, metabolism, and disease. Cell, 2017, 168(6), 960-976.
[http://dx.doi.org/10.1016/j.cell.2017.02.004] [PMID: 28283069]
[2]
Polivka, J., Jr; Janku, F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther., 2014, 142(2), 164-175.
[http://dx.doi.org/10.1016/j.pharmthera.2013.12.004] [PMID: 24333502]
[3]
Cooray, S. The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival. J. Gen. Virol., 2004, 85(Pt 5), 1065-1076.
[http://dx.doi.org/10.1099/vir.0.19771-0] [PMID: 15105524]
[4]
Shin, Y-K.; Liu, Q.; Tikoo, S.K.; Babiuk, L.A.; Zhou, Y. Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation. J. Gen. Virol., 2007, 88(Pt 3), 942-950.
[http://dx.doi.org/10.1099/vir.0.82483-0] [PMID: 17325368]
[5]
Buchkovich, N.J.; Yu, Y.; Zampieri, C.A.; Alwine, J.C. The TORrid affairs of viruses: Effects of mammalian DNA viruses on the PI3K-Akt-mTOR signalling pathway. Nat. Rev. Microbiol., 2008, 6(4), 266-275.
[http://dx.doi.org/10.1038/nrmicro1855] [PMID: 18311165]
[6]
Shaw, R.J.; Cantley, L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 2006, 441(7092), 424-430.
[http://dx.doi.org/10.1038/nature04869] [PMID: 16724053]
[7]
Engelman, J.A.; Luo, J.; Cantley, L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet., 2006, 7(8), 606-619.
[http://dx.doi.org/10.1038/nrg1879] [PMID: 16847462]
[8]
Alessi, D.R.; Pearce, L.R.; García-Martínez, J.M. New insights into mTOR signaling: mTORC2 and beyond. Sci. Signal., 2009, 2(67), pe27.
[http://dx.doi.org/10.1126/scisignal.267pe27] [PMID: 19383978]
[9]
Thomson, A.W.; Turnquist, H.R.; Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol., 2009, 9(5), 324-337.
[http://dx.doi.org/10.1038/nri2546] [PMID: 19390566]
[10]
Säemann, M.D.; Haidinger, M.; Hecking, M.; Hörl, W.H.; Weichhart, T. The multifunctional role of mTOR in innate immunity: Implica-tions for transplant immunity. Am. J. Transplant., 2009, 9(12), 2655-2661.
[http://dx.doi.org/10.1111/j.1600-6143.2009.02832.x] [PMID: 19788500]
[11]
Sun, Q.; Liu, Q.; Zheng, Y.; Cao, X. Rapamycin suppresses TLR4-triggered IL-6 and PGE(2) production of colon cancer cells by inhibit-ing TLR4 expression and NF-kappaB activation. Mol. Immunol., 2008, 45(10), 2929-2936.
[http://dx.doi.org/10.1016/j.molimm.2008.01.025] [PMID: 18343502]
[12]
Duvoux, C.; Toso, C. 2015.
[13]
Au, K.P.; Chok, K.S.H. Mammalian target of rapamycin inhibitors after post-transplant hepatocellular carcinoma recurrence: Is it too late? World J. Gastrointest. Surg., 2020, 12(4), 149-158.
[http://dx.doi.org/10.4240/wjgs.v12.i4.149] [PMID: 32426094]
[14]
Conti, P.; Ronconi, G.; Caraffa, A.; Gallenga, C.E.; Ross, R.; Frydas, I.; Kritas, S.K. 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), 327-331.
[PMID: 32171193]
[15]
Diao, B.; Wang, C.; Tan, Y.; Chen, X.; Liu, Y.; Ning, L. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Medrxiv, 2020.
[http://dx.doi.org/10.1101/2020.02.18.20024364]
[16]
Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu, W.; Xie, X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; Gao, H.; Guo, L.; Xie, J.; Wang, G.; Jiang, R.; Gao, Z.; Jin, Q.; Wang, J.; Cao, B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020, 395(10223), 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[17]
Sahebnasagh, A.; Mojtahedzadeh, M.; Najmeddin, F.; Najafi, A.; Safdari, M.; Rezai Ghaleno, H.; Habtemariam, S.; Berindan-Neagoe, I.; Nabavi, S.M. A perspective on erythropoietin as a potential adjuvant therapy for acute lung injury/acute respiratory distress syndrome in patients with covid-19. Arch. Med. Res., 2020, 51(7), 631-635.
[http://dx.doi.org/10.1016/j.arcmed.2020.08.002] [PMID: 32863034]
[18]
Chen, Y.; Liang, W.; Yang, S.; Wu, N.; Gao, H.; Sheng, J.; Yao, H.; Wo, J.; Fang, Q.; Cui, D.; Li, Y.; Yao, X.; Zhang, Y.; Wu, H.; Zheng, S.; Diao, H.; Xia, S.; Zhang, Y.; Chan, K.H.; Tsoi, H.W.; Teng, J.L.; Song, W.; Wang, P.; Lau, S.Y.; Zheng, M.; Chan, J.F.; To, K.K.; Chen, H.; Li, L.; Yuen, K.Y. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: Clinical analysis and char-acterisation of viral genome. Lancet, 2013, 381(9881), 1916-1925.
[http://dx.doi.org/10.1016/S0140-6736(13)60903-4] [PMID: 23623390]
[19]
Channappanavar, R.; Perlman, S. Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immuno-pathology. Semin. Immunopathol., 2017, 39(5), 529-539.
[20]
Murray, J.L.; McDonald, N.J.; Sheng, J.; Shaw, M.W.; Hodge, T.W.; Rubin, D.H.; O’Brien, W.A.; Smee, D.F. Inhibition of influenza A virus replication by antagonism of a PI3K-AKT-mTOR pathway member identified by gene-trap insertional mutagenesis. Antivir. Chem. Chemother., 2012, 22(5), 205-215.
[http://dx.doi.org/10.3851/IMP2080] [PMID: 22374988]
[21]
Kindrachuk, J.; Ork, B.; Hart, B.J.; Mazur, S.; Holbrook, M.R.; Frieman, M.B.; Traynor, D.; Johnson, R.F.; Dyall, J.; Kuhn, J.H.; Olinger, G.G.; Hensley, L.E.; Jahrling, P.B. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respira-tory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob. Agents Chemother., 2015, 59(2), 1088-1099.
[http://dx.doi.org/10.1128/AAC.03659-14] [PMID: 25487801]
[22]
Ye, L.; Lee, J.; Xu, L.; Mohammed, A.U.; Li, W.; Hale, J.S.; Tan, W.G.; Wu, T.; Davis, C.W.; Ahmed, R.; Araki, K. mTOR promotes anti-viral humoral immunity by differentially regulating CD4 helper T cell and B cell responses. J. Virol., 2017, 91(4), e01653-e16.
[http://dx.doi.org/10.1128/JVI.01653-16] [PMID: 27974559]
[23]
Turner, A.P.; Shaffer, V.O.; Araki, K.; Martens, C.; Turner, P.L.; Gangappa, S.; Ford, M.L.; Ahmed, R.; Kirk, A.D.; Larsen, C.P. Sirolimus enhances the magnitude and quality of viral-specific CD8+ T-cell responses to vaccinia virus vaccination in rhesus macaques. Am. J. Transplant., 2011, 11(3), 613-618.
[http://dx.doi.org/10.1111/j.1600-6143.2010.03407.x] [PMID: 21342450]
[24]
Wang, C-H.; Chung, F-T.; Lin, S-M.; Huang, S-Y.; Chou, C-L.; Lee, K-Y.; Lin, T.Y.; Kuo, H.P. Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit. Care Med., 2014, 42(2), 313-321.
[http://dx.doi.org/10.1097/CCM.0b013e3182a2727d] [PMID: 24105455]
[25]
Zheng, Y.; Li, R.; Liu, S. S. Immunoregulation with mTOR inhibitors to prevent COVID-19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines. J. Med. Virol., 2020, 92(9), 1495-1500.
[http://dx.doi.org/10.1002/jmv.26009]
[26]
Zhou, Y.; Hou, Y.; Shen, J.; Huang, Y.; Martin, W.; Cheng, F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov., 2020, 6(1), 14.
[http://dx.doi.org/10.1038/s41421-020-0153-3] [PMID: 33723226]
[27]
Guillen, E.; Pineiro, G.J.; Revuelta, I.; Rodriguez, D.; Bodro, M.; Moreno, A.; Campistol, J.M.; Diekmann, F.; Ventura-Aguiar, P. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am. J. Transplant., 2020, 20(7), 1875-1878.
[http://dx.doi.org/10.1111/ajt.15874] [PMID: 32198834]
[28]
Piao, S.G.; Bae, S.K.; Lim, S.W.; Song, J-H.; Chung, B.H.; Choi, B.S.; Yang, C.W. Drug interaction between cyclosporine and mTOR in-hibitors in experimental model of chronic cyclosporine nephrotoxicity and pancreatic islet dysfunction. Transplantation, 2012, 93(4), 383-389.
[http://dx.doi.org/10.1097/TP.0b013e3182421604] [PMID: 22267156]
[29]
Lam, H.; Jeffery, J.; Sitar, D.S.; Aoki, F.Y. Oseltamivir, an influenza neuraminidase inhibitor drug, does not affect the steady-state phar-macokinetic characteristics of cyclosporine, mycophenolate, or tacrolimus in adult renal transplant patients. Ther. Drug Monit., 2011, 33(6), 699-704.
[http://dx.doi.org/10.1097/FTD.0b013e3182399448] [PMID: 22105586]

Rights & Permissions Print Cite
Article Metrics
18
1
© 2024 Bentham Science Publishers | Privacy Policy