Zinc and SARS‑CoV‑2: A molecular modeling study of Zn interactions with RNA‑dependent RNA‑polymerase and 3C‑like proteinase enzymes

Pormohammad,Ali; Monych,Nadia K.; Turner,Raymond J.

doi:10.3892/ijmm.2020.4790

Zinc and SARS‑CoV‑2: A molecular modeling study of Zn interactions with RNA‑dependent RNA‑polymerase and 3C‑like proteinase enzymes

Authors:
- Ali Pormohammad
- Nadia K. Monych
- Raymond J. Turner
View Affiliations

Affiliations: Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N4V8, Canada
Published online on: November 18, 2020 https://doi.org/10.3892/ijmm.2020.4790
Pages: 326-334
Copyright: © Pormohammad et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

RNA‑dependent RNA‑polymerase (RdRp) and 3C‑like proteinase (3CLpro) are two main enzymes that play a key role in the replication of SARS‑CoV‑2. Zinc (Zn) has strong immunogenic properties and is known to bind to a number of proteins, modulating their activities. Zn also has a history of use in viral infection control. Thus, the present study models potential Zn binding to RdRp and the 3CLpro. Through molecular modeling, the Zn binding sites in the aforementioned two important enzymes of viral replication were found to be conserved between severe acute respiratory syndrome (SARS)‑coronavirus (CoV) and SARS‑CoV‑2. The location of these sites may influence the enzymatic activity of 3CLpro and RdRp in coronavirus disease 2019 (COVID‑19). Since Zn has established immune health benefits, is readily available, non‑expensive and a safe food supplement, with the comparisons presented here between SARS‑CoV and COVID‑19, the present study proposes that Zn could help ameliorate the disease process of COVID‑19 infection.

View Figures

View References

1	Beyersmann D and Haase H: Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals. 14:331–341. 2001. View Article : Google Scholar
2	Marreiro D do N, Cruz KJ, Morais JB, Beserra JB, Severo JS and Soares de Oliveira AR: Zinc and oxidative stress: Current mechanisms. Antioxidants (Basel). 6:242017. View Article : Google Scholar
3	Maywald M, Wessels I and Rink L: Zinc signals and immunity. Int J Mol Sci. 18:22222017. View Article : Google Scholar :
4	Miller BD and Welch RM: Food system strategies for preventing micronutrient malnutrition. Food Policy. Wolters Kluwer-Medknow Publications; pp. 115–128. 2013, View Article : Google Scholar
5	Kochańczyk T, Drozd A and Krężel A: Relationship between the architecture of zinc coordination and zinc binding affinity in proteins-Insights into zinc regulation. Metallomics. 7:244–257. 2015. View Article : Google Scholar
6	Prasad AS: Impact of the discovery of human zinc deficiency on health. J Am Coll Nutr. 28:257–265. 2009. View Article : Google Scholar
7	Read SA, Obeid S, Ahlenstiel C and Ahlenstiel G: The role of zinc in antiviral immunity. Adv Nutr. 10:696–710. 2019. View Article : Google Scholar : PubMed/NCBI
8	Korant BD and Butterworth BE: Inhibition by zinc of rhinovirus protein cleavage: Interaction of zinc with capsid polypeptides. J Virol. 18:298–306. 1976. View Article : Google Scholar : PubMed/NCBI
9	Kaushik N, Subramani C, Anang S, Muthumohan R, Shalimar, Nayak B, Ranjith-Kumar CT and Surjit M: Zinc salts block hepatitis E virus replication by inhibiting the activity of viral RNA-dependent RNA polymerase. J Virol. 91:e00754–e00717. 2017. View Article : Google Scholar : PubMed/NCBI
10	Korant BD, Kauer JC and Butterworth BE: Zinc ions inhibit replication of rhinoviruses. Nature. 248:588–590. 1974. View Article : Google Scholar : PubMed/NCBI
11	te Velthuis AJ, van den Worml SH, Sims AC, Baric RS, Snijder EJ and van Hemert MJ: Zn²⁺ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 6:e10011762010. View Article : Google Scholar
12	Hsu JTA, Kuo CJ, Hsieh HP, Wang YC, Huang KK, Lin CPC, Huang PF, Chen X and Liang PH: Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV. FEBS Lett. 574:116–120. 2004. View Article : Google Scholar : PubMed/NCBI
13	Lee CC, Kuo CJ, Hsu MF, Liang PH, Fang JM, Shie JJ and Wang AH: Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors. FEBS Lett. 581:5454–5458. 2007. View Article : Google Scholar : PubMed/NCBI
14	Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld FJ and Seipelt J: Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J Virol. 83:58–64. 2009. View Article : Google Scholar :
15	Lanke K, Krenn BM, Melchers WJ, Seipelt J and van Kuppeveld FJ: PDTC inhibits picornavirus polyprotein processing and RNA replication by transporting zinc ions into cells. J Gen Virol. 88:1206–1217. 2007. View Article : Google Scholar : PubMed/NCBI
16	Geist FC, Bateman JA and Hayden FG: In vitro activity of zinc salts against human rhinoviruses. Antimicrob Agents Chemother. 31:622–624. 1987. View Article : Google Scholar : PubMed/NCBI
17	Hung M, Gibbs CS and Tsiang M: Biochemical characterization of rhinovirus RNA-dependent RNA polymerase. Antiviral Res. 56:99–114. 2002. View Article : Google Scholar : PubMed/NCBI
18	Krenn BM, Holzer B, Gaudernak E, Triendl A, van Kuppeveld FJ and Seipelt J: Inhibition of polyprotein processing and RNA replication of human rhinovirus by pyrrolidine dithiocarbamate involves metal ions. J Virol. 79:13892–13899. 2005. View Article : Google Scholar : PubMed/NCBI
19	Suara RO and Crowe JE: Effect of zinc salts on respiratory syncytial virus replication. Antimicrob Agents Chemother. 48:783–790. 2004. View Article : Google Scholar : PubMed/NCBI
20	Srivastava V, Rawall S, Vijayan VK and Khanna M: Influenza a virus induced apoptosis: Inhibition of DNA laddering & caspase-3 activity by zinc supplementation in cultured HeLa cells. Indian J Med Res. 129:579–586. 2009.PubMed/NCBI
21	Ghaffari H, Tavakoli A, Moradi A, Tabarraei A, Bokharaei-Salim F, Zahmatkeshan M, Farahmand M, Javanmard D, Kiani SJ, Esghaei M, et al: Inhibition of H1N1 influenza virus infection by zinc oxide nanoparticles: Another emerging application of nanomedicine. J Biomed Sci. 26:702019. View Article : Google Scholar : PubMed/NCBI
22	Shankar AH and Prasad AS: Zinc and immune function: The biological basis of altered resistance to infection. Am J Clin Nutr. 68(Suppl 2): 447S–463S. 1998. View Article : Google Scholar : PubMed/NCBI
23	Hulisz D: Efficacy of zinc against common cold viruses: An overview. J Am Pharm Assoc 2003. 44:594–603. 2004. View Article : Google Scholar : PubMed/NCBI
24	Hemilä H, Fitzgerald JT, Petrus EJ and Prasad A: Zinc acetate lozenges may improve the recovery rate of common cold patients: An individual patient data meta-analysis. Open Forum Infect Dis. 4:ofx0592017. View Article : Google Scholar : PubMed/NCBI
25	Science M, Johnstone J, Roth DE, Guyatt G and Loeb M: Zinc for the treatment of the common cold: A systematic review and meta-analysis of randomized controlled trials. CMAJ. 184:E551–E561. 2012. View Article : Google Scholar : PubMed/NCBI
26	D'Cruze H, Arroll B and Kenealy T: Is intranasal zinc effective and safe for the common cold? A systematic review and meta-analysis. J Prim Health Care. 1:134–139. 2009. View Article : Google Scholar : PubMed/NCBI
27	Caruso TJ, Prober CG and Gwaltney JM Jr: Treatment of naturally acquired common colds with zinc: A structured review. Clin Infect Dis. 45:569–574. 2007. View Article : Google Scholar : PubMed/NCBI
28	Zhou Y, Hou Y, Shen J, Huang Y, Martin W and Cheng F: Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 6:142020. View Article : Google Scholar : PubMed/NCBI
29	Lung J, Lin YS, Yang YH, Chou YL, Shu LH, Cheng YC, Liu HT and Wu CY: The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase. J Med Virol. 92:693–697. 2020. View Article : Google Scholar : PubMed/NCBI
30	Prentice E, McAuliffe J, Lu X, Subbarao K and Denison MR: Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins. J Virol. 78:9977–9986. 2004. View Article : Google Scholar : PubMed/NCBI
31	Fan K, Wei P, Feng Q, Chen S, Huang C, Ma L, Lai B, Pei J, Liu Y, Chen J and Lai L: Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase. J Biol Chem. 279:1637–1642. 2004. View Article : Google Scholar
32	Subissi L, Imbert I, Ferron F, Collet A, Coutard B, Decroly E and Canard B: SARS-CoV ORF1b-encoded nonstructural proteins 12-16: Replicative enzymes as antiviral targets. Antiviral Res. 101:122–130. 2014. View Article : Google Scholar
33	Wu YS, Lin WH, Hsu JT and Hsieh HP: Antiviral drug discovery against SARS-CoV. Curr Med Chem. 13:2003–2020. 2006. View Article : Google Scholar : PubMed/NCBI
34	Kirchdoerfer RN and Ward AB: Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat Commun. 10:23422019. View Article : Google Scholar : PubMed/NCBI
35	Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, Wang T, Sun Q, Ming Z, Zhang L, et al: Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 368:779–782. 2020. View Article : Google Scholar : PubMed/NCBI
36	Mesecar AD; Center for Structural Genomics of Infectious Diseases (CSGID): RCSB PDB-6W63: Structure of COVID-19 main protease bound to potent broad-spectrum non-covalent inhibitor X77. National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID); 2020
37	Nitulescu GM, Paunescu H, Moschos SA, Petrakis D, Nitulescu G, Ion GND, Spandidos DA, Nikolouzakis TK, Drakoulis N and Tsatsakis A: Comprehensive analysis of drugs to treat SARS-CoV-2 infection: Mechanistic insights into current COVID-19 therapies (Review). Int J Mol Med. 46:467–488. 2020. View Article : Google Scholar : PubMed/NCBI
38	Lee CC, Kuo CJ, Ko TP, Hsu MF, Tsui YC, Chang SC, Yang S, Chen SJ, Chen HC, Hsu MC, et al: Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds. J Biol Chem. 284:7646–7655. 2009. View Article : Google Scholar : PubMed/NCBI
39	Pormohammad A, Ghorbani S, Khatami A, Farzi R, Baradaran B, Turner DL, Turner RJ, Bahr NC and Idrovo JP: Comparison of confirmed COVID-19 with SARS and MERS cases-clinical characteristics, laboratory findings, radiographic signs and outcomes: A systematic review and meta-analysis. Rev Med Virol. 30:e21122020. View Article : Google Scholar
40	Pormohammad A, Ghorbani S, Khatami A, Razizadeh MH, Alborzi E, Zarei M, Idrovo JP and Turner RJ: Comparison of influenza type A and B with COVID-19: A global systematic review and meta-analysis on clinical, laboratory and radio-graphic findings. Rev Med Virol. Oct 9–2020.Epub ahead of print. View Article : Google Scholar
41	Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, Sun R, Tian Z, Xu X and Wei H: Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev. Mar 13–2020.Epub ahead of print. View Article : Google Scholar
42	Conti P, Ronconi G, Caraffa A, Gallenga C, Ross R, Frydas I and Kritas S: 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. 34:327–331. 2020.PubMed/NCBI
43	Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, Bucci E, Piacentini M, Ippolito G and Melino G: COVID-19 infection: The perspectives on immune responses. Cell Death Differ. 27:14512020. View Article : Google Scholar : PubMed/NCBI
44	Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS and Manson JJ; HLH Across Speciality Collaboration, UK: COVID-19: Consider cytokine storm syndromes and immuno-suppression. Lancet. 395:1033–1034. 2020. View Article : Google Scholar : PubMed/NCBI
45	Skalny AV, Rink L, Ajsuvakova OP, Aschner M, Gritsenko VA, Alekseenko SI, Svistunov AA, Petrakis D, Spandidos DA, Aaseth J, et al: Zinc and respiratory tract infections: Perspectives for CoviD'19 (Review). Int J Mol Med. 46:17–26. 2020.PubMed/NCBI
46	Wessels I, Rolles B and Rink L: The potential impact of zinc supplementation on COVID-19 pathogenesis. Front Immunol. 11:17122020. View Article : Google Scholar : PubMed/NCBI
47	Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D and Richardson P: COVID-19: Combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 20:400–402. 2020. View Article : Google Scholar : PubMed/NCBI
48	Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R and Caporali R: COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmun Rev. 19:1025232020. View Article : Google Scholar : PubMed/NCBI
49	Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, Wang J, Qin Y, Zhang X, Yan X, et al: The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China. Clin Immunol. 214:1083932020. View Article : Google Scholar
50	Gammoh NZ and Rink L: Zinc in infection and inflammation. Nutrients. 9:6242017. View Article : Google Scholar :
51	Jarosz M, Olbert M, Wyszogrodzka G, Młyniec K and Librowski T: Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling. Inflammopharmacology. 25:11–24. 2017. View Article : Google Scholar : PubMed/NCBI
52	Knoell DL, Smith DA, Sapkota M, Heires AJ, Hanson CK, Smith LM, Poole JA, Wyatt TA and Romberger DJ: Insufficient zinc intake enhances lung inflammation in response to agricultural organic dust exposure. J Nutr Biochem. 70:56–64. 2019. View Article : Google Scholar : PubMed/NCBI
53	Fischer KJ, Yajjala VK, Bansal S, Bauer C, Chen R and Sun K: Monocytes represent one source of bacterial shielding from antibiotics following influenza virus infection. J Immunol. 202:2027–2034. 2019. View Article : Google Scholar : PubMed/NCBI
54	Zhang L, Forst CV, Gordon A, Gussin G, Geber AB, Fernandez PJ, Ding T, Lashua L, Wang M, Balmaseda A, et al: Characterization of antibiotic resistance and host-microbiome interactions in the human upper respiratory tract during influenza infection. Microbiome. 8:392020. View Article : Google Scholar : PubMed/NCBI
55	Llor C and Bjerrum L: Antimicrobial resistance: Risk associated with antibiotic overuse and initiatives to reduce the problem. Ther Adv Drug Saf. 5:229–241. 2014. View Article : Google Scholar : PubMed/NCBI
56	Kostoff RN, Briggs MB, Porter AL, Hernández AF, Abdollahi M, Aschner M and Tsatsakis A: The under-reported role of toxic substance exposures in the COVID-19 pandemic. Food Chem Toxicol. 145:1116872020. View Article : Google Scholar : PubMed/NCBI
57	Çaǧlayan Serin D, Pullukçu H, Çiçek C, Sipahi OR, Taşbakan S, Atalay S and Pneumonia Study Group: Bacterial and viral etiology in hospitalized community acquired pneumonia with molecular methods and clinical evaluation. J Infect Dev Ctries. 8:510–518. 2014. View Article : Google Scholar
58	Matson MJ, Stock F, Shupert WL, Bushmaker T, Feldmann F, Bishop WB, Frank KM, Dekker JP, Chertow DS and Munster VJ: Compatibility of maximum-containment virus-inactivation protocols with identification of bacterial coinfections by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J Infect Dis. 218(Suppl 5): S297–S300. 2018. View Article : Google Scholar : PubMed/NCBI
59	Stevens MP, Patel PK and Nori P: Involving antimicrobial stewardship programs in COVID-19 response efforts: All hands on deck. Infect Control Hosp Epidemiol. 41:744–745. 2020. View Article : Google Scholar : PubMed/NCBI
60	Essack S, Bell J, Burgoyne DS, Duerden M and Shephard A: Topical (local) antibiotics for respiratory infections with sore throat: An antibiotic stewardship perspective. J Clin Pharm Ther. 44:829–837. 2019. View Article : Google Scholar : PubMed/NCBI
61	Sohrabi C, Alsafi Z, O'Neill N, Khan M, Kerwan A, Al-Jabir A, Iosifidis C and Agha R: World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg. 76:71–76. 2020. View Article : Google Scholar : PubMed/NCBI
62	Denny KJ, De Wale J, Laupland KB, Harris PNA and Lipman J: When not to start antibiotics: Avoiding antibiotic overuse in the intensive care unit. Clin Microbiol Infect. 26:35–40. 2020. View Article : Google Scholar
63	Song Z, Hu Y, Zheng S, Yang L and Zhao R: Hospital pharmacists' pharmaceutical care for hospitalized patients with COVID-19: Recommendations and guidance from clinical experience. Res Social Adm Pharm. Apr 3–2020.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
64	Gupta S, Sakhuja A, Kumar G, McGrath E, Nanchal RS and Kashani KB: Culture-negative severe sepsis: Nationwide trends and outcomes. Chest. 150:1251–1259. 2016. View Article : Google Scholar : PubMed/NCBI
65	Lemire JA, Harrison JJ and Turner RJ: Antimicrobial activity of metals: Mechanisms, molecular targets and applications. Nat Rev Microbiol. 11:371–384. 2013. View Article : Google Scholar : PubMed/NCBI
66	Turner RJ, Gugala N and Lemire J: Can metals replace traditional antibiotics? Adjac Gov. November;46–47. 2016.
67	Lemire JA and Turner RJ: Mechanisms underlying the anti-microbial capacity of metals. Stress and Environmental Regulation of Gene Expression and Adaptation in Bacteria. John Wiley & Sons, Inc; Hoboken, NJ: pp. 215–224. 2016, View Article : Google Scholar
68	Turner RJ: Metal-based antimicrobial strategies. Microb Biotechnol. 10:1062–1065. 2017. View Article : Google Scholar : PubMed/NCBI
69	Monych NK, Gugala N and Turner RJ: Chapter 9. Metal-based Antimicrobials. Antimicrobial Materials for Biomedical Applications. Thomas Graham House; Cambridge: pp. 252–276. 2019, View Article : Google Scholar
70	Gugala N, Lemire JA and Turner RJ: The efficacy of different anti-microbial metals at preventing the formation of, and eradicating bacterial biofilms of pathogenic indicator strains. J Antibiot (Tokyo). 70:775–780. 2017. View Article : Google Scholar
71	Jesline A, John NP, Narayanan PM, Vani C and Murugan S: Antimicrobial activity of zinc and titanium dioxide nanoparticles against biofilm-producing methicillin-resistant Staphylococcus aureus. Appl Nanosci. 5:157–162. 2015. View Article : Google Scholar
72	Wang X, Du Y and Liu H: Preparation, characterization and anti-microbial activity of chitosan-Zn complex. Carbohydr Polym. 56:21–26. 2004. View Article : Google Scholar
73	Gugala N, Vu D, Parkins MD and Turner RJ: Specificity in the susceptibilities of escherichia coli, pseudomonas aeruginosa and Staphylococcus aureus clinical isolates to six metal antimicrobials. Antibiotics (Basel). 8:512019. View Article : Google Scholar
74	National Institutes of Health: Vitamin K - Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/vita-minK-HealthProfessional/urisimplehttps://ods.od.nih.gov/factsheets/vita-minK-HealthProfessional/ Accessed June 3, 2020.
75	Plum LM, Rink L and Hajo H: The essential toxin: Impact of zinc on human health. Int J Environ Res Public Health. 7:1342–1365. 2010. View Article : Google Scholar : PubMed/NCBI