Generic placeholder image

Mini-Reviews in Medicinal Chemistry


ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Possible Targets and Therapies of SARS-CoV-2 Infection

Author(s): Kasturi Sarkar, Parames C. Sil, Seyed Fazel Nabavi, Ioana Berindan-Neagoe, Cosmin Andrei Cismaru, Seyed Mohammad Nabavi and Solomon Habtemariam*

Volume 20 , Issue 18 , 2020

Page: [1900 - 1907] Pages: 8

DOI: 10.2174/1389557520666200807131855

Price: $65


The global spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes COVID-19 has become a source of grave medical and socioeconomic concern to human society. Since its first appearance in the Wuhan region of China in December 2019, the most effective measures of managing the spread of SARS-CoV-2 infection have been social distancing and lockdown of human activity; the level of which has not been seen in our generations. Effective control of the viral infection and COVID-19 will ultimately depend on the development of either a vaccine or therapeutic agents. This article highlights the progresses made so far in these strategies by assessing key targets associated with the viral replication cycle. The key viral proteins and enzymes that could be targeted by new and repurposed drugs are discussed.

Keywords: COVID-19, SARS-CoV-2, infection cycle, structural proteins, non-structural proteins, RNA dependent RNA polymerase, proteases, helicase, nucleosides.

Graphical Abstract
Spychalski, P.; Błażyńska-Spychalska, A.; Kobiela, J. Estimating case fatality rates of COVID-19. Lancet Infect. Dis., In Press
[] [PMID: 32243815]
Drake, J.W.; Holland, J.J. Mutation rates among RNA viruses. Proc. Natl. Acad. Sci. USA, 1999, 96(24), 13910-13913.
[] [PMID: 10570172]
Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B, In Press
[] [PMID: 32292689]
Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; Bi, Y.; Ma, X.; Zhan, F.; Wang, L.; Hu, T.; Zhou, H.; Hu, Z.; Zhou, W.; Zhao, L.; Chen, J.; Meng, Y.; Wang, J.; Lin, Y.; Yuan, J.; Xie, Z.; Ma, J.; Liu, W.J.; Wang, D.; Xu, W.; Holmes, E.C.; Gao, G.F.; Wu, G.; Chen, W.; Shi, W.; Tan, W. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet, 2020, 395(10224), 565-574.
[] [PMID: 32007145]
Mousavizadeh, L.; Ghasemi, S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J. Microbiol. Immunol. Infect., In Press
[] [PMID: 32265180]
Siu, Y.L.; Teoh, K.T.; Lo, J.; Chan, C.M.; Kien, F.; Escriou, N.; Tsao, S.W.; Nicholls, J.M.; Altmeyer, R.; Peiris, J.S.; Bruzzone, R.; Nal, B. The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles. J. Virol., 2008, 82(22), 11318-11330.
[] [PMID: 18753196]
Li, F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol., 2016, 3(1), 237-261.
[] [PMID: 27578435]
Walls, A.C.; Park, Y.J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 2020, 181(2), 281-292.e6.
[] [PMID: 32155444]
Schoeman, D.; Fielding, B.C. Coronavirus envelope protein: Current knowledge. Virol. J., 2019, 16(1), 69.
[] [PMID: 31133031]
Lee, E.Y.P.; Ng, M.Y.; Khong, P.L. COVID-19 pneumonia: What has CT taught us? Lancet Infect. Dis., 2020, 20(4), 384-385.
[] [PMID: 32105641]
Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; Zhao, Y.; Li, Y.; Wang, X.; Peng, Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-Infected pneumonia in wuhan, China. JAMA, 2020, 323(11), 1061-1069.
[] [PMID: 32031570]
Naicker, S.; Yang, C.W.; Hwang, S.J.; Liu, B.C.; Chen, J.H.; Jha, V. The novel coronavirus 2019 epidemic and kidneys. Kidney Int., 2020, 97(5), 824-828.
[] [PMID: 32204907]
Du, L.; He, Y.; Zhou, Y.; Liu, S.; Zheng, B.J.; Jiang, S. The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nat. Rev. Microbiol., 2009, 7(3), 226-236.
[] [PMID: 19198616]
Wong, S.K.; Li, W.; Moore, M.J.; Choe, H.; Farzan, M. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J. Biol. Chem., 2004, 279(5), 3197-3201.
[] [PMID: 14670965]
Gui, M.; Song, W.; Zhou, H.; Xu, J.; Chen, S.; Xiang, Y.; Wang, X. Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding. Cell Res., 2017, 27(1), 119-129.
[] [PMID: 28008928]
Gorbalenya, A.E.; Donchenko, A.P.; Blinov, V.M.; Koonin, E.V. Cysteine proteases of positive strand RNA viruses and chymotrypsin-like serine proteases. A distinct protein superfamily with a common structural fold. FEBS Lett., 1989, 243(2), 103-114.
[] [PMID: 2645167]
Elfiky, A.A. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci., 2020, •••248117477
[] [PMID: 32119961]
Kirchdoerfer, R.N.; Ward, A.B. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat. Commun., 2019, 10(1), 2342.
[] [PMID: 31138817]
Posthuma, C.C.; Te Velthuis, A.J.W.; Snijder, E.J. Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes. Virus Res., 2017, 234, 58-73.
[] [PMID: 28174054]
Gao, Y.; Yab, L.; Huang, Y.; Liu, F.; Zhao, Y.; Cao, L.; Wang, T. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, 2020.
Imbert, I.; Guillemot, J.C.; Bourhis, J.M.; Bussetta, C.; Coutard, B.; Egloff, M.P.; Ferron, F.; Gorbalenya, A.E.; Canard, B. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J., 2006, 25(20), 4933-4942.
[] [PMID: 17024178]
Zhang, L.; Lin, D.; Sun, X.; Curth, U.; Drosten, C.; Sauerhering, L.; Becker, S.; Rox, K.; Hilgenfeld, R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 2020, 368(6489), 409-412.
[] [PMID: 32198291]
Liu, X.; Zhang, B.; Jin, Z.; Yang, H.; Rao, Z. The crystal structure of COVID-19 main protease in complex with an inhibitor N3 PDB Database,
Singleton, M.R.; Dillingham, M.S.; Wigley, D.B. Structure and mechanism of helicases and nucleic acid translocases. Annu. Rev. Biochem., 2007, 76, 23-50.
[] [PMID: 17506634]
Jia, Z.; Yan, L.; Ren, Z.; Wu, L.; Wang, J.; Guo, J.; Zheng, L.; Ming, Z.; Zhang, L.; Lou, Z.; Rao, Z. Delicate structural coordination of the Severe Acute Respiratory Syndrome coronavirus Nsp13 upon ATP hydrolysis. Nucleic Acids Res., 2019, 47(12), 6538-6550.
[] [PMID: 31131400]
Mirza, M.U.; Froeyen, M. Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against Main protease, Nsp12 RNA-dependent RNA polymerase and Nsp13 helicase. Virology, In Press
Xue, X.; Yu, H.; Yang, H.; Xue, F.; Wu, Z.; Shen, W.; Li, J.; Zhou, Z.; Ding, Y.; Zhao, Q.; Zhang, X.C.; Liao, M.; Bartlam, M.; Rao, Z. Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design. J. Virol., 2008, 82(5), 2515-2527.
[] [PMID: 18094151]
Warren, T.K.; Jordan, R.; Lo, M.K.; Ray, A.S.; Mackman, R.L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H.C.; Larson, N.; Strickley, R.; Wells, J.; Stuthman, K.S.; Van Tongeren, S.A.; Garza, N.L.; Donnelly, G.; Shurtleff, A.C.; Retterer, C.J.; Gharaibeh, D.; Zamani, R.; Kenny, T.; Eaton, B.P.; Grimes, E.; Welch, L.S.; Gomba, L.; Wilhelmsen, C.L.; Nichols, D.K.; Nuss, J.E.; Nagle, E.R.; Kugelman, J.R.; Palacios, G.; Doerffler, E.; Neville, S.; Carra, E.; Clarke, M.O.; Zhang, L.; Lew, W.; Ross, B.; Wang, Q.; Chun, K.; Wolfe, L.; Babusis, D.; Park, Y.; Stray, K.M.; Trancheva, I.; Feng, J.Y.; Barauskas, O.; Xu, Y.; Wong, P.; Braun, M.R.; Flint, M.; McMullan, L.K.; Chen, S.S.; Fearns, R.; Swaminathan, S.; Mayers, D.L.; Spiropoulou, C.F.; Lee, W.A.; Nichol, S.T.; Cihlar, T.; Bavari, S. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature, 2016, 531(7594), 381-385.
[] [PMID: 26934220]
Manns, M.P.; Wedemeyer, H.; Cornberg, M. Treating viral hepatitis C: Efficacy, side effects, and complications. Gut, 2006, 55(9), 1350-1359.
[] [PMID: 16905701]
Sidwell, R.W.; Barnard, D.L. Respiratory syncytial virus infections: Recent prospects for control. Antiviral Res., 2006, 71(2-3), 379-390.
[] [PMID: 16806515]
Furuta, Y.; Komeno, T.; Nakamura, T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci., 2017, 93(7), 449-463.
[] [PMID: 28769016]
Khungar, V.; Han, S.H. A systematic review of side effects of nucleoside and nucleotide drugs used for treatment of chronic hepatitis B. Curr. Hepat. Rep., 2010, 9(2), 75-90.
[] [PMID: 20461127]
Chan, L.; Das, S.K.; Reddy, T.J.; Poisson, C.; Proulx, M.; Pereira, O.; Courchesne, M.; Roy, C.; Wang, W.; Siddiqui, A.; Yannopoulos, C.G.; Nguyen-Ba, N.; Labrecque, D.; Bethell, R.; Hamel, M.; Courtemanche-Asselin, P.; L’Heureux, L.; David, M.; Nicolas, O.; Brunette, S.; Bilimoria, D.; Bédard, J. Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 1: Sulfonamides. Bioorg. Med. Chem. Lett., 2004, 14(3), 793-796.
[] [PMID: 14741291]
Eltahla, A.A.; Luciani, F.; White, P.A.; Lloyd, A.R.; Bull, R.A. Inhibitors of the hepatitis C Virus Polymerase; Mode of action and resistance. Viruses, 2015, 7(10), 5206-5224.
[] [PMID: 26426038]
Kneteman, N.M.; Howe, A.Y.; Gao, T.; Lewis, J.; Pevear, D.; Lund, G.; Douglas, D.; Mercer, D.F.; Tyrrell, D.L.; Immermann, F.; Chaudhary, I.; Speth, J.; Villano, S.A.; O’Connell, J.; Collett, M. HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus. Hepatology, 2009, 49(3), 745-752.
[] [PMID: 19072827]
Shi, S.T.; Herlihy, K.J.; Graham, J.P.; Nonomiya, J.; Rahavendran, S.V.; Skor, H.; Irvine, R.; Binford, S.; Tatlock, J.; Li, H.; Gonzalez, J.; Linton, A.; Patick, A.K.; Lewis, C. Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob. Agents Chemother., 2009, 53(6), 2544-2552.
[] [PMID: 19307358]
Yi, G.; Deval, J.; Fan, B.; Cai, H.; Soulard, C.; Ranjith-Kumar, C.T.; Smith, D.B.; Blatt, L.; Beigelman, L.; Kao, C.C. Biochemical study of the comparative inhibition of hepatitis C virus RNA polymerase by VX-222 and filibuvir. Antimicrob. Agents Chemother., 2012, 56(2), 830-837.
[] [PMID: 22143520]
Liu, X.; Wang, X.J. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J. Genet. Genomics, 2020, 47(2), 119-121.
[] [PMID: 32173287]
Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res., 2020, 30(3), 269-271.
[] [PMID: 32020029]
Vincent, M.J.; Bergeron, E.; Benjannet, S.; Erickson, B.R.; Rollin, P.E.; Ksiazek, T.G.; Seidah, N.G.; Nichol, S.T. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol. J., 2005, 2, 69.
[] [PMID: 16115318]
Lentini, G.; Cavalluzzi, M.M.; Habtemariam, S. COVID-19, Chloroquine repurposing, and cardiac safety concern: Chirality Might Help. Molecules, 2020, 25(8), 1834.
[] [PMID: 32316270]
Adedeji, A.O.; Marchand, B.; Te Velthuis, A.J.; Snijder, E.J.; Weiss, S.; Eoff, R.L.; Singh, K.; Sarafianos, S.G. Mechanism of nucleic acid unwinding by SARS-CoV helicase. PLoS One, 2012, 7(5)e36521
[] [PMID: 22615777]
Briguglio, I.; Piras, S.; Corona, P.; Carta, A. Inhibition of RNA helicases of ssRNA(+) Virus belonging to flaviviridae, coronaviridae and picornaviridae families. Int. J. Med. Chem., 2011, 2011213135
[] [PMID: 27516903]
Tanner, J.A.; Zheng, B.J.; Zhou, J.; Watt, R.M.; Jiang, J.Q.; Wong, K.L.; Lin, Y.P.; Lu, L.Y.; He, M.L.; Kung, H.F.; Kesel, A.J.; Huang, J.D. The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus. Chem. Biol., 2005, 12(3), 303-311.
[] [PMID: 15797214]
de Wit, E.; Feldmann, F.; Okumura, A.; Horne, E.; Haddock, E.; Saturday, G.; Scott, D.; Erlandson, K.J.; Stahl, N.; Lipsich, L.; Kyratsous, C.A.; Feldmann, H. Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets. Antiviral Res., 2018, 156, 64-71.
[] [PMID: 29885377]
Siti, K.; Kurniawan, H.; Awaluddin, R.; Suhartati, S. Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints, 2020, 2020030226
Li, Y.; Xu, T.; Lin, Z.; Wang, C.; Xia, Y.; Guo, M. Inhibition of enterovirus A71 by selenium nanoparticles interferes with JNK signaling pathways. ACS Omega, 2019, 4, 6720-6725.
Li, Y.; Lin, Z.; Gong, G.; Guo, M.; Xu, T.; Wang, C. Inhibition of H1N1 influenza virus-induced apoptosis by selenium nanoparticles functionalized with arbidol through ROS-mediated signaling pathways. J. Mater. Chem. B Mater. Biol. Med., 2019, 7, 4252-4262.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy