Identification and characterization of malaria box compounds possessing inhibition effect on the SARS-CoV-2 spike protein
Keywords:
B-cell epitope, malaria box, molecular docking, SARS-CoV-2, spike proteinAbstract
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections and deaths worldwide since 2019. Although current treatments are available for patients with mild-to-moderate symptoms, they have limited efficacy in severe COVID-19 and can cause side effects in some patient groups, particularly in older or nonhealthy individuals. Developing new drugs that can better manage severe disease, reduce mortality rates, and broaden the treatment options are necessary.
Objective:To evaluate the binding interactions and inhibitory effect of malaria box compounds on the B-cell epitope regions of SARS-CoV-2 spike protein.
Methods: Molecular docking of 400 malaria box compounds against the predicted B-cell epitopes of the spike protein was performed. The inhibitory effects of malaria box compounds on the spike RBD were determined using competitive enzyme-linked immunoassay. The binding affinity between malaria box compounds and non-RBD epitopes was examined by surface plasmon resonance (SPR) assays.
Results: MMV000563 and MMV019690 were the top-scoring compounds that could bind to the spike RBD, with inhibitory effects at 45.6% and 47.0%, respectively. However, competitive ELISA revealed that the binding of the spike RBD to human angiotensin-converting enzyme 2 was most strongly inhibited by MMV665881 (P = 0.004). Based on SPR results, MMV019881, MMV020912, and MMV000753 showed the highest binding affinities to their respective epitope peptides in the non-RBD regions of the spike protein.
Conclusion: These results demonstrate the ability of malaria box compounds to bind to and interfere with SARS-CoV-2 spike protein, which may be beneficial for COVID-19 treatment.
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References
Stróż S, Kosiorek P, Stasiak-Barmuta A. The COVID-19 inflammation and high mortality mechanism trigger. Immunogenetics 2024;76:15-25.
https://doi.org/10.1007/s00251-023-01326-4
Parra-Lucares A, Segura P, Rojas V, Pumarino C, SaintPierre G, Toro L. Emergence of SARS-CoV-2 Variants in the world: How could this happen?. Life (Basel) 2022;12:194.
https://doi.org/10.3390/life12020194
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020;579:265-69.
https://doi.org/10.1038/s41586-020-2008-3
Malik YA. Properties of coronavirus and SARS-CoV-2. Malays J Pathol 2020;42:3-11.
Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-nCoV. Biochem Biophys Res Commun 2020;525:135-40.
https://doi.org/10.1016/j.bbrc.2020.02.071
Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215-20.
https://doi.org/10.1038/s41586-020-2180-5
Peter EK, Schug A. The inhibitory effect of a coronavirus spike protein fragment with ACE2. Biophys J 2021;119:1001-10.
https://doi.org/10.1016/j.bpj.2020.08.022
Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B 2020;10:766-88.
https://doi.org/10.1016/j.apsb.2020.02.008
Lim HX, Masomian M, Khalid K, Kumar AU, MacAry PA, Poh CL. Identification of B-Cell epitopes for eliciting neutralizing antibodies against the SARS-CoV-2 spike protein through bioinformatics and monoclonal antibody targeting. Int J Mol Sci 2022;23:4341.
https://doi.org/10.3390/ijms23084341
Polyiam K, Phoolcharoen W, Butkhot N, Srisaowakarn C, Thitithanyanont A, Auewarakul P, et al. Immunodominant linear B cell epitopes in the spike and membrane proteins of SARS-CoV-2 identified by immunoinformatics prediction and immunoassay. Sci Rep 2021;11:20383.
https://doi.org/10.1038/s41598-021-99642-w
Boehm E, Kronig I, Neher RA, Eckerle I, Vetter P, Kaiser L. Novel SARS-CoV-2 variants: the pandemics within the pandemic. Clin Microbiol Infect 2021;27:1109-17.
https://doi.org/10.1016/j.cmi.2021.05.022
Feng B, Fu K. Latest development of approved COVID-19 drugs and COVID-19 drugs undergoing late stage clinical trials. Front. Drug Discov 2023;3:1304129.
https://doi.org/10.3389/fddsv.2023.1304129
Thiruchelvam K, Kow CS, Hadi MA, Hasan SS. The use of remdesivir for the management of patients with moderate-to-severe COVID-19: a systematic review. Expert Rev Anti Infect Ther 2022;20:211-29.
https://doi.org/10.1080/14787210.2021.1949984
Lewnard JA, McLaughlin JM, Malden D, Hong V, Puzniak L, Ackerson BK, et al. Effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and deaths in People with COVID-19: a cohort study
in a large US health-care system. Lancet Infect Dis 2023;23:806-15.
https://doi.org/10.1016/S1473-3099(23)00118-4
Tr seid M, Arribas JR, Assoumou L, Holten AR, Poissy J, Terziã V, et al. Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebocontrolled phase 3 trial. Crit Care 2023;27:9.
https://doi.org/10.1186/s13054-022-04205-8
Rosas IO, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in hospitalized patients with severe Covid-19 Pneumonia. N Engl J Med 2021;384:1503-16.
https://doi.org/10.1056/NEJMoa2028700
Parvathaneni V, Kulkarni NS, Muth A, Gupta V. Drug repurposing: a promising tool to accelerate the drug discovery process. Drug Discov Today 2019;24:2076-85.
https://doi.org/10.1016/j.drudis.2019.06.014
Pruijssers AJ, George AS, Schäfer A, Leist SR, Gralinksi LE, Dinnon KH 3rd, et al. Remdesivir inhibits SARSCoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA Polymerase in mice.Cell Rep 2020;32:107940.
https://doi.org/10.1016/j.celrep.2020.107940
Ansems K, Grundeis F, Dahms K, Mikolajewska A, Thieme V, Piechotta V, et al. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev 2023;1:CD014962.
https://doi.org/10.1002/14651858.CD014962.pub2
Hashemian SMR, Sheida A, Taghizadieh M, Memar MY, Hamblin MR, Bannazadeh Baghi H, et al. Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy? Biomed Pharmacother 2023;162:114367.
https://doi.org/10.1016/j.biopha.2023.114367
Zhang X, Zhang Y, Qiao W, Zhang J, Qi Z. Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19. Int Immunopharmacol 2020;86:106749.
https://doi.org/10.1016/j.intimp.2020.106749
Raiteri A, Piscaglia F, Granito A, Tovoli F. Tocilizumab: From Rheumatic Diseases to COVID-19. Curr Pharm Des 2021;27:1597-607.
https://doi.org/10.2174/1381612827666210311141512
Barnette KG, Gordon MS, Rodriguez D, Bird TG, Skolnick A, Schnaus M, et al. Oral sabizabulin for highrisk, hospitalized adults with Covid-19: Interim analysis. NEJM Evid 2022;1:EVIDoa2200145.
https://doi.org/10.1056/EVIDoa2200145
Noreen S, Maqbool I, Madni A. Dexamethasone: Therapeutic potential, risks, and future projection during COVID-19 pandemic. Eur J Pharmacol 2021;894:173854.
https://doi.org/10.1016/j.ejphar.2021.173854
Gendrot M, Andreani J, Boxberger M, Jardot P, FontaI, Le Bideau M, et al. Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation. Travel Med Infect Dis 2020;37:101873.
https://doi.org/10.1016/j.tmaid.2020.101873
Mahévas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: Results of a study using routinely collected data to emulate a target trial. medRxiv 2020;20060699.
https://doi.org/10.1136/bmj.m1844
Lamiable A, Thévenet P, Rey J, Vavrusa M, Derreumaux P, Tufféry P. PEP-FOLD3: Faster de novo structure prediction for linear peptides in solution and in complex. Nucleic Acids Res 2016;44(W1):W449-W54.
https://doi.org/10.1093/nar/gkw329
Shen Y, Maupetit J, Derreumaux P, Tufféry P. Improved PEP-FOLD approach for peptide and miniprotein structure prediction. J Chem Theory Comput 2014;10:4745-58.
https://doi.org/10.1021/ct500592m
Thévenet P, Shen Y, Maupetit J, Guyon F, Derreumaux P, Tufféry P. PEP-FOLD: an updated de novo structure prediction server for both linear and disulfide bonded cyclic peptides. Nucleic Acids Res 2012;40(Web Server issue):W288-93.
https://doi.org/10.1093/nar/gks419
Hsu KC, Chen YF, Lin SR, Yang JM. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics 2011;12 Suppl 1(Suppl1):S33.
https://doi.org/10.1186/1471-2105-12-S1-S33
Fong KY, Sandlin RD, Wright DW. Identification of â-hematin inhibitors in the MMV Malaria Box. Int J Parasitol Drugs Drug Resist 2015;5:84-91.
https://doi.org/10.1016/j.ijpddr.2015.05.003
Lucantoni L, Duffy S, Adjalley SH, Fidock DA, Avery VM. Identification of MMV Malaria Box inhibitors of Plasmodium falciparum early-stage gametocytes using a luciferase-based high-throughput assay. Antimicrob Agents Chemother 2013;57:6050-62.
https://doi.org/10.1128/AAC.00870-13
Duffy S, Avery VM. Identification of inhibitors of Plasmodium falciparum gametocyte development. Malar J 2013;12:408.
https://doi.org/10.1186/1475-2875-12-408
Sun W, Tanaka TQ, Magle CT, Huang W, Southall N, Huang R, et al. Chemical signatures and new drugtargets for gametocytocidal drug development. Sci Rep 2014;4:3743.
https://doi.org/10.1038/srep03743
Bowman JD, Merino EF, Brooks CF, Striepen B, Carlier PR, Cassera MB. Antiapicoplast and gametocytocidal screening to identify the mechanisms of action of compounds within the malaria box. Antimicrob Agents Chemother 2014;58:811-9.
https://doi.org/10.1128/AAC.01500-13
Linares M, Viera S, Crespo B, Franco V, Gómez-Lorenzo MG, Jiménez-Díaz MB, et al. Identifying rapidly parasiticidal anti-malarial drugs using a simple and reliable in vitro parasite viability fast assay. Malar J 2015;14:441.
https://doi.org/10.1186/s12936-015-0962-2
Paiardini A, Bamert RS, Kannan-Sivaraman K, Drinkwater N, Mistry SN, Scammells PJ, et al. Screening the medicines for malaria venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18. PloS One 2015;10:e0115859.
https://doi.org/10.1371/journal.pone.0115859
von Koschitzky I, Gerhardt H, Lämmerhofer M, Kohout M, Gehringer M, Laufer S, et al. New insights into novel inhibitors against deoxyhypusine hydroxylase from plasmodium falciparum: compounds with an iron chelating potential. Amino Acids 2015;47:1155-66.
https://doi.org/10.1007/s00726-015-1943-z
Ramsey NB, Andersen OS. Bilayer effects of antimalarial compounds. PloS One 2015;10:e0142401.
https://doi.org/10.1371/journal.pone.0142401
Chatterjee S, Bhattacharya M, Nag S, Dhama K, Chakraborty C. A detailed overview of SARS-CoV-2 omicron: Its sub-variants, mutations and pathophysiology, clinical characteristics, immunological landscape, immune escape, and therapies. Viruses 2023; 15:167.
https://doi.org/10.3390/v15010167
Wu L, Zhou L, Mo M, Liu T, Wu C, Gong C, et al. SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2. Signal Transduct Target Ther 2022;7:8.
https://doi.org/10.1038/s41392-021-00863-2
Cattin-Ortolá J, Welch LG, Maslen SL, Papa G, James LC, Munro S. Sequences in the cytoplasmic tail of SARS-CoV-2 spike facilitate expression at the cell surface and syncytia formation. Nat Commun 2021;12:5333.
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