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
Research Article

Molecular Interactions of Zyesami with the SARS-CoV-2 nsp10/nsp16 Protein Complex

Author(s): Sultan F. Alnomasy*, Bader S. Alotaibi, Ziyad M. Aldosari, Ahmed H. Mujamammi, Ahmad Alzamami, Pragya Anand, Yusuf Akhter, Farhan R. Khan and Mohammad R. Hasan

Volume 26, Issue 6, 2023

Published on: 12 October, 2022

Page: [1196 - 1203] Pages: 8

DOI: 10.2174/1386207325666220816141028

Price: $65

Abstract

Background: SARS-CoV-2 emerged in late 2019 and caused COVID-19. Patients treated with Zyesami were found to have a 3-fold decrease in respiratory failure and improved clinical outcomes. It was reported that Zyesami inhibits RNA replication of SARS-CoV-2, including several non-structural proteins essential in viral RNA replication. SARS-CoV-2 is a distinctive virus that requires nsp10 and nsp16 for its methyltransferases activity which is crucial for RNA stability and protein synthesis.

Objective: We aimed the in silico determination of inhibitory consequences of Zyesami on the SARS-CoV-2 nsp10/nsp16 complex. Targeting SARS-CoV-2 nsp10/ nsp16 protein complex may be used to develop a drug against COVID-19.

Methods: I-TASSER was used for secondary structure prediction of Zyesami. CABS-dock was used to model Zyesami with SARS-CoV-2 nsp16 interaction. The docked complex was visualized using PyMol. The quality of the docking model was checked by using ProQdock.

Results: The 3D structure of SARS-CoV 2, nsp10/nsp16 showed that essential interactions exist between nsp10 and nsp16. Significant contact areas of Zyesami exist across amino acid residues of nsp10; Asn40-Thr47, Val57-Pro59, Gly69-Ser72, Cys77-Pro84, Lys93-Tyr96. In addition, polar contacts between nsp16 and Zyesami are Asn299-Ser440, Val297-Asn443, Gly149-Tyr437, Gln159-Lys430, Asn178- Arg429, Ser146-Arg429, Ser146-Arg429, Lys147-Arg429, Asr221-Thr422, Lys183-Asp423, Lys183-Asp423, and Gln219-Asp423 the residues are shown of nsp16 and Zyesami respectively.

Conclusion: The structural bioinformatics analyses have indicated the potential binding specificity of Zyesami and nsp16. Data predict how the initial binding of Zyesami with nsp10 and nsp16 may occur. Moreover, this binding could significantly inhibit the 2 -O-MTase activity of the SARSCoV nsp10/16 complex.

Keywords: COVID-19, SARS-CoV-2, microbiology, zyesami, coronavirus, nsp16, nsp10.

« Previous Next »
Graphical Abstract

[1]
Zumla, A.; Chan, JFW.; Azhar, EI.; Hui, DSC.; Yuen, K-Y. Coronaviruses - drug discovery and therapeutic options. Nat. Rev. Drug Discov., 2016, 15(5), 327-347.
[http://dx.doi.org/10.1038/nrd.2015.37] [PMID: 26868298]
[2]
Chan, JFW.; Chan, K-H.; Kao, RYT.; To, KKW.; Zheng, B-J.; Li, CPY. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J. Infect., 2013, 67(6), 606-616.
[http://dx.doi.org/10.1016/j.jinf.2013.09.029] [PMID: 24096239]
[3]
Dyall, J.; Coleman, C.M.; Hart, B.J.; Venkataraman, T.; Holbrook, M.R.; Kindrachuk, J.; Johnson, R.F.; Olinger, G.G., Jr; Jahrling, P.B.; Laidlaw, M.; Johansen, L.M.; Lear-Rooney, C.M.; Glass, P.J.; Hensley, L.E.; Frieman, M.B. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob. Agents Chemother., 2014, 58(8), 4885-4893.
[http://dx.doi.org/10.1128/AAC.03036-14] [PMID: 24841273]
[4]
Omrani, AS.; Saad, MM.; Baig, K.; Bahloul, A.; Abdul-Matin, M.; Alaidaroos, AY. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect. Dis., 2014, 14(11), 1090-1095.
[http://dx.doi.org/10.1016/S1473-3099(14)70920-X] [PMID: 25278221]
[5]
Temerozo, J.R.; Sacramento, C.Q.; Fintelman-Rodrigues, N.; Pão, C.R.R.; de Freitas, C.S.; da Silva Gomes Dias, S. The neuropeptides VIP and PACAP inhibit SARS-CoV-2 replication in monocytes and lung epithelial cells, decrease production of proinflammatory cytokines, and VIP levels are associated with survival in severe Covid-19 patients. bioRxiv, 2020, 2020.07.25.220806.
[6]
Moody, T.W.; Ito, T.; Osefo, N.; Jensen, R.T. VIP and PACAP: Recent insights into their functions/roles in physiology and disease from molecular and genetic studies. Curr. Opin. Endocrinol. Diabetes Obes., 2011, 18(1), 61-67.
[http://dx.doi.org/10.1097/MED.0b013e328342568a] [PMID: 21157320]
[7]
Said, S.I.; Mutt, V. Polypeptide with broad biological activity: Isolation from small intestine. Science, 1970, 169(3951), 1217-1218.
[http://dx.doi.org/10.1126/science.169.3951.1217] [PMID: 5450698]
[8]
Miyata, A.; Arimura, A.; Dahl, R.R.; Minamino, N.; Uehara, A.; Jiang, L.; Culler, M.D.; Coy, D.H. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem. Biophys. Res. Commun., 1989, 164(1), 567-574.
[http://dx.doi.org/10.1016/0006-291X(89)91757-9] [PMID: 2803320]
[9]
Harmar, A.J.; Fahrenkrug, J.; Gozes, I.; Laburthe, M.; May, V.; Pisegna, J.R.; Vaudry, D.; Vaudry, H.; Waschek, J.A.; Said, S.I. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br. J. Pharmacol., 2012, 166(1), 4-17.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01871.x] [PMID: 22289055]
[10]
Datta, P.K.; Liu, F.; Fischer, T.; Rappaport, J.; Qin, X. SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy. Theranostics, 2020, 10(16), 7448-7464.
[http://dx.doi.org/10.7150/thno.48076] [PMID: 32642005]
[11]
Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; Wang, X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 2020, 581(7807), 215-220.
[http://dx.doi.org/10.1038/s41586-020-2180-5] [PMID: 32225176]
[12]
Alnomasy, S.F. Virus-receptor interactions of SARS-CoV-2 spikereceptor-binding domain and human neuropilin-1 b1 domain. Saudi J. Biol. Sci., 2021, 28(7), 3926-3928.
[http://dx.doi.org/10.1016/j.sjbs.2021.03.074] [PMID: 33850424]
[13]
Chen, Y.; Cai, H.; Pan, J.; Xiang, N.; Tien, P.; Ahola, T.; Guo, D. Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc. Natl. Acad. Sci. USA, 2009, 106(9), 3484-3489.
[http://dx.doi.org/10.1073/pnas.0808790106] [PMID: 19208801]
[14]
Bouvet, M.; Debarnot, C.; Imbert, I.; Selisko, B.; Snijder, E.J.; Canard, B.; Decroly, E. In vitro reconstitution of SARS-coronavirus mRNA cap methylation. PLoS Pathog., 2010, 6(4), e1000863.
[http://dx.doi.org/10.1371/journal.ppat.1000863] [PMID: 20421945]
[15]
von Grotthuss, M.; Wyrwicz, L.S.; Rychlewski, L. mRNA cap-1 methyltransferase in the SARS genome. Cell, 2003, 113(6), 701-702.
[http://dx.doi.org/10.1016/S0092-8674(03)00424-0] [PMID: 12809601]
[16]
Bollati, M.; Milani, M.; Mastrangelo, E.; Ricagno, S.; Tedeschi, G.; Nonnis, S.; Decroly, E.; Selisko, B.; de Lamballerie, X.; Coutard, B.; Canard, B.; Bolognesi, M. Recognition of RNA cap in the Wesselsbron virus NS5 methyltransferase domain: Implications for RNA-capping mechanisms in Flavivirus. J. Mol. Biol., 2009, 385(1), 140-152.
[http://dx.doi.org/10.1016/j.jmb.2008.10.028] [PMID: 18976670]
[17]
Kurcinski, M.; Jamroz, M.; Blaszczyk, M.; Kolinski, A.; Kmiecik, S. CABS-dock web server for the flexible docking of peptides to proteins without prior knowledge of the binding site. Nucleic Acids Res., 2015, 43(W1), W419-24.
[http://dx.doi.org/10.1093/nar/gkv456] [PMID: 25943545]
[18]
Basu, S.; Wallner, B. Finding correct protein-protein docking models using ProQDock. Bioinformatics, 2016, 32(12), i262-i270.
[http://dx.doi.org/10.1093/bioinformatics/btw257] [PMID: 27307625]
[19]
Chen, Y.; Guo, D. Molecular mechanisms of coronavirus RNA capping and methylation. Virol. Sin., 2016, 31(1), 3-11.
[http://dx.doi.org/10.1007/s12250-016-3726-4] [PMID: 26847650]
[20]
Chen, Y.; Su, C.; Ke, M.; Jin, X.; Xu, L.; Zhang, Z. Biochemical and structural insights into the mechanisms of SARS coronavirus RNA ribose 2′-O-methylation by nsp16/nsp10 protein complex. PLoS Pathog., 2011, 7(10), e1002294.
[http://dx.doi.org/10.1371/journal.ppat.1002294] [PMID: 22022266]
[21]
Imbert, I.; Snijder, E.J.; Dimitrova, M.; Guillemot, J-C.; Lécine, P.; Canard, B. The SARS-Coronavirus PLnc domain of nsp3 as a replication/transcription scaffolding protein. Virus Res., 2008, 133(2), 136-148.
[http://dx.doi.org/10.1016/j.virusres.2007.11.017] [PMID: 18255185]
[22]
Pan, Ja.; Peng, X.; Gao, Y.; Li, Z.; Lu, X.; Chen, Y. Genome-wide analysis of protein-protein interactions and involvement of viral proteins in SARS-CoV replication. PLoS One, 2008, 3(10), e3299.
[http://dx.doi.org/10.1371/journal.pone.0003299] [PMID: 18827877]
[23]
Ke, M.; Chen, Y.; Wu, A.; Sun, Y.; Su, C.; Wu, H. Short peptides derived from the interaction domain of SARS coronavirus nonstructural protein nsp10 can suppress the 2′-O-methyltransferase activity of nsp10/nsp16 complex. Virus Res., 2012, 167(2), 322-328.
[http://dx.doi.org/10.1016/j.virusres.2012.05.017] [PMID: 22659295]
[24]
Krafcikova, P.; Silhan, J.; Nencka, R.; Boura, E. Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin. Nat. Commun., 2020, 11(1), 3717.
[http://dx.doi.org/10.1038/s41467-020-17495-9] [PMID: 32709887]
[25]
Laurini, E.; Marson, D.; Aulic, S.; Fermeglia, M.; Pricl, S. Computational alanine scanning and structural analysis of the SARS-CoV-2 spikeprotein/angiotensin-converting enzyme 2 complex. ACS Nano, 2020, 14(9), 11821-11830.
[http://dx.doi.org/10.1021/acsnano.0c04674] [PMID: 32833435]
[26]
Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; Müller, M.A.; Drosten, C.; Pöhlmann, S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 2020, 181(2), 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[27]
Letko, M.; Marzi, A.; Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat. Microbiol., 2020, 5(4), 562-569.
[http://dx.doi.org/10.1038/s41564-020-0688-y] [PMID: 32094589]
[28]
Tian, X.; Li, C.; Huang, A.; Xia, S.; Lu, S.; Shi, Z.; Lu, L.; Jiang, S.; Yang, Z.; Wu, Y.; Ying, T. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg. Microbes Infect., 2020, 9(1), 382-385.
[http://dx.doi.org/10.1080/22221751.2020.1729069] [PMID: 32065055]
[29]
Daly, J.L.; Simonetti, B.; Klein, K.; Chen, K.E.; Williamson, M.K.; Antón-Plágaro, C.; Shoemark, D.K.; Simón-Gracia, L.; Bauer, M.; Hollandi, R.; Greber, U.F.; Horvath, P.; Sessions, R.B.; Helenius, A.; Hiscox, J.A.; Teesalu, T.; Matthews, D.A.; Davidson, A.D.; Collins, B.M.; Cullen, P.J.; Yamauchi, Y. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science, 2020, 370(6518), 861-865.
[http://dx.doi.org/10.1126/science.abd3072] [PMID: 33082294]
[30]
Cantuti-Castelvetri, L.; Ojha, R.; Pedro, L.D.; Djannatian, M.; Franz, J.; Kuivanen, S.; van der Meer, F.; Kallio, K.; Kaya, T.; Anastasina, M.; Smura, T.; Levanov, L.; Szirovicza, L.; Tobi, A.; Kallio-Kokko, H.; Österlund, P.; Joensuu, M.; Meunier, F.A.; Butcher, S.J.; Winkler, M.S.; Mollenhauer, B.; Helenius, A.; Gokce, O.; Teesalu, T.; Hepojoki, J.; Vapalahti, O.; Stadelmann, C.; Balistreri, G.; Simons, M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science, 2020, 370(6518), 856-860.
[http://dx.doi.org/10.1126/science.abd2985] [PMID: 33082293]
[31]
Choudhary, S.; Malik, YS. Tomar, S Identification of SARS-CoV-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach. Front. Immunol., 2020, 11, 1664.
[http://dx.doi.org/10.3389/fimmu.2020.01664] [PMID: 32754161]
[32]
Fatma, B.; Kumar, R.; Singh, VA.; Nehul, S.; Sharma, R.; Kesari, P. Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection. Antiviral Res., 2020, 179, 104808.
[http://dx.doi.org/10.1016/j.antiviral.2020.104808] [PMID: 32380148]
[33]
Wan, Y.; Shang, J.; Graham, R.; Baric, R.S.; Li, F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J. Virol., 2020, 94(7), e00127-e20.
[http://dx.doi.org/10.1128/JVI.00127-20] [PMID: 31996437]
[34]
Clark, M.J.; Miduturu, C.; Schmidt, A.G.; Zhu, X.; Pitts, J.D.; Wang, J.; Potisopon, S.; Zhang, J.; Wojciechowski, A.; Hann Chu, J.J.; Gray, N.S.; Yang, P.L. GNF2 inhibits dengue virus by targeting Abl kinases and the viral e protein. Cell Chem. Biol., 2016, 23(4), 443-452.
[http://dx.doi.org/10.1016/j.chembiol.2016.03.010] [PMID: 27105280]
[35]
Chakraborty, A.; Koldobskiy, M.A.; Bello, N.T.; Maxwell, M.; Potter, J.J.; Juluri, K.R.; Maag, D.; Kim, S.; Huang, A.S.; Dailey, M.J.; Saleh, M.; Snowman, A.M.; Moran, T.H.; Mezey, E.; Snyder, S.H. Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Cell, 2010, 143(6), 897-910.
[http://dx.doi.org/10.1016/j.cell.2010.11.032] [PMID: 21145457]
[36]
Cheng, H.; Lear-Rooney, C.M.; Johansen, L.; Varhegyi, E.; Chen, Z.W.; Olinger, G.G.; Rong, L. Inhibition of ebola and marburg virus entry by G protein coupled receptor antagonists. J. Virol., 2015, 89(19), 9932-9938.
[http://dx.doi.org/10.1128/JVI.01337-15] [PMID: 26202243]

Rights & Permissions Print Cite
Article Metrics
27
2
© 2024 Bentham Science Publishers | Privacy Policy