Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein ORF8

Document Type : Original article

Authors

Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran

Abstract

The recent pernicious COVID-19 pandemic is caused by SARS-CoV-2. While most therapeutic strategies have focused on the viral spike protein, Open Reading Frame 8 (ORF8) plays a critical role in causing the severity of the disease. Nonetheless, there still needs to be more information on the ORF8 binding epitopes and their appropriate safe inhibitors. Herein, the protein binding sites were detected through comprehensive structural analyses. The validation of the binding sites was investigated through protein conservation analysis and blind docking. The potential natural product (NP) inhibitors were selected based on a structure-function approach. The solo and combined inhibition functions of these NPs were examined through molecular docking studies. Two binding epitopes were identified, one between the ORF8 monomers (DGBM) and the other on the surface (Gal1-Like). E92 was predicted to be pivotal for DGBM, and R101 for Gal1-like, which was then confirmed through molecular dockings. The inhibitory effects of selected phytochemical (Artemisinin), bacterial (Ivermectin), and native-liken (DEG-168) NPs were compared with the Remdesivir. Selected NPs showed solo- and co-functionality against Remdesivir to inhibit functional regions of the ORF8 structure. The DGBM is highly engaged in capturing the NPs. Additionally, the co-functionality study of NPs showed that the Ivermectin-DEG168 combination has the strongest mechanism for inhibiting all the predicted binding sites. Ivermectin can interfere with ORF8-MHC-I interaction through inhibition of A51 and F120. Two new binding sites on this non-infusion protein structure were introduced using a combination of approaches. Additionally, three safe and effective were found to inhibit these binding sites.

Keywords

References

  1. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020;55: 105924.
  2. Sohrabi C, Alsafi Z, O’Neill N, Khan M, Kerwan A, Al-Jabir A, Iosifidis C, Agha R. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg 2020;76:71-76.
  3. Kandeel M, Ibrahim A, Fayez M, Al-Nazawi M. From SARS and MERS CoVs to SARS-CoV-2: Moving toward more biased codon usage in viral structural and nonstructural genes. J Med Virol 2020;92:660-666.
  4. Vinjamuri S, Li L, Bouvier M. SARS-CoV-2 ORF8: One protein, seemingly one structure, and many functions. Front Immunol 2022;13:1035559.
  5. Jungreis I, Sealfon R, Kellis M. SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes. Nat Commun 2021;12:2642.
  6. Gong YN, Tsao KC, Hsiao MJ, Huang CG, Huang PN, Huang PW, Lee KM, Liu YC, Yang SL, Kuo RL, Chen KF, Liu YC, Huang SY, Huang HI, Liu MT, Yang JR, Chiu CH, Yang CT, Chen GW, Shih SR. SARS-CoV-2 genomic surveillance in Taiwan revealed novel ORF8-deletion mutant and clade possibly associated with infections in Middle East. Emerg Microbes Infect 2020;9:1457-1466.
  7. Young BE, Fong SW, Chan YH, Mak TM, Ang LW, Anderson DE, Lee CYP, Amrun SN, Lee B, Goh YS, Su YCF, Wei WE, Kalimuddin S, Chai LYA, Pada S, Tan SY, Sun L, Parthasarathy P, Chen YYC, Barkham T, Lin RTP, Maurer-Stroh S, Leo YS, Wang LF, Renia L, Lee VJ, Smith GJD, Lye DC, Ng LF. Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study. Lancet 2020;396:603-611.
  8. Nagy Á, Pongor S, Győrffy B. Different mutations in SARS-CoV-2 associate with severe and mild outcome. Int J Antimicrob Agents 2021;57:106272.
  9. Valcarcel A, Bensussen A, Álvarez-Buylla ER, Díaz J. Structural Analysis of SARS-CoV-2 ORF8 Protein: Pathogenic and Therapeutic Implications. Front Genet 2021;12:693227.
  10. Islam S, Parves MR, Islam MJ, Ali MA, Efaz FM, Hossain MS, Ullah MO, Halim MA. Structural and functional effects of the L84S mutant in the SARS-COV-2 ORF8 dimer based on microsecond molecular dynamics study. J Biomol Struct Dyn 2024;42:5770-5787.
  11. Oostra M, de Haan CAM, Rottier PJM. The 29-nucleotide deletion present in human but not in animal severe acute respiratory syndrome coronaviruses disrupts the functional expression of open reading frame 8. J Virol 2007;81:13876-13888.
  12. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Huttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Hass K, Modak M, Kim M, Hass P, Palacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett M, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Kain AM, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu YF, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Sadat Savar N, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, Von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, Garcia-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020;583:459-468.
  13. Díaz J. SARS-CoV-2 Molecular Network Structure. Front Physiol 2020;11:870.
  14. Fahmi M, Kitagawa H, Yasui G, Kubota Y, Ito M. The Functional Classification of ORF8 in SARS-CoV-2 Replication, Immune Evasion, and Viral Pathogenesis Inferred through Phylogenetic Profiling. Evol Bioinform Online 2021;17:11769343211003079.
  15. Kumar S, Nyodu R, Maurya VK, Saxena SK. Host Immune Response and Immunobiology of Human SARS-CoV-2 Infection. Coronavirus Disease 2019 (COVID-19) 2020;43-53.
  16. Li JY, Liao CH, Wang Q, Tan YJ, Luo R, Qiu Y, Ge XY. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res 2020;286:198074.
  17. Rashid F, Dzakah EE, Wang H, Tang S. The ORF8 protein of SARS-CoV-2 induced endoplasmic reticulum stress and mediated immune evasion by antagonizing production of interferon beta. Virus Res 2021;296:198350.
  18. Wang X, Wang W, Wang T, Wang J, Jiang Y, Wang X, Qiu Z, Feng N, Sun W, Li C, Yang S, Xia X, He H, Gao Y. SARS-CoV-2 ORF8 Protein Induces Endoplasmic Reticulum Stress-like Responses and Facilitates Virus Replication by Triggering Calnexin: an Unbiased Study. J Virol 2023;97:e0001123.
  19. Zhang Y, Chen Y, Li Y, Huang F, Luo B, Yuan Y, Xia B, Ma X, Yang T, Yu F, Liu J, Liu B, Song Z, Chen J, Yan S, Wu L, Pan T, Zhang X, Li R, Huang W, He X, Xiao F, Zhang J, Zhang H. The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι. Proc Natl Acad Sci U S A 2021;118.e2024202118.
  20. Chaudhari AM, Singh I, Joshi M, Patel A, Joshi C. Defective ORF8 dimerization in delta variant of SARS CoV2 leads to abrogation of ORF8 MHC-I interaction and overcome suppression of adaptive immune response. bioRxiv 2021;2021.08.24.457457.
  21. Kriplani N, Clohisey S, Fonseca S, Fletcher S, Lee HM, Ashworth J, Kurian D, Lycett S, Tait-Burkard C, Baillie JK, Woolhouse MJ, Carding SR, Stewart JP, Digard P. Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages. bioRxiv 2021;2021.08.13.456266.
  22. Lin X, Fu B, Yin S, Li Z, Liu H, Zhang H, Xing N, Wang Y, Xue W, Xiong Y, Zhang S, Zhao Q, Xu S, Zhang J, Wang P, Nian W, Wang X, Wu H. ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway. iScience 2021;24: 102293.
  23. Lin X, Fu B, Xiong Y, Xing N, Xue W, Guo D, Zaky M, Pavani K, Kunec D, Trimpert J, Wu H. Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection. PLoS Pathog 2023;19: e1011128.
  24. Hamdorf M, Imhof T, Bailey-Elkin B, Betz J, Theobald SJ, Simonis A, Di Cristanziano V, Gieselmann L, Dewald F, Lehmann C, Augustin M, Klein F, Alejandre Alcazar MA, Rongisch R, Fabri M, Rybniker J, Goebel H, Stetefeld J, Brachvogel B, Cursiefen C, Koch M, Bock F. The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm. J Mol Cell Biol 2024;15:mjad062.
  25. Garmeh Motlagh F, Azimzadeh Irani M, Masoomi Nomandan SZ, Assadizadeh M. Computational design and investigation of the monomeric spike SARS-CoV-2-ferritin nanocage vaccine stability and interactions. Front Mol Biosci 2024;11:1403635.
  26. Hachim A, Kavian N, Cohen CA, Chin AWH, Chu DKW, Mok CKP, Tsang OTY, Yeung YC, Perera RAP, Poon LLM, Peiris JSM, Valkenburg SA. ORF8 and ORF3b antibodies are accurate serological markers of early and late SARS-CoV-2 infection. Nat Immunol 2020;21:1293-1301.
  27. Wenzhong L, Hualan L. COVID-19: ORF8 Synthesizes Nitric Oxide to Break the Blood-Brain/Testi Barrier and Damage the Reproductive System. ChemRxiv 2021.
  28. Hsia CC. Respiratory function of hemoglobin. N Engl J Med 1998;338:239-247.
  29. Su YCF, Anderson DE, Young BE, Linster M, Zhu F, Jayakumar J, Zhuang Y, Kalimuddin S, Low JGH, Tan CW, Chia WN, Mak TM, Octavia S, Chavatte JM, Lee RTC, Pada S, Tan SY, Sun L, Yan GZ, Maurer-Stroh S, Mendenhall IH, Leo YS, Lye DC, Wang LF, Smith GJD. Discovery and Genomic Characterization of a 382-Nucleotide Deletion in ORF7b and ORF8 during the Early Evolution of SARS-CoV-2. MBio 2020;11.e01610-e01620.
  30. Chen X, Zhou Z, Huang C, Zhou Z, Kang S, Huang Z, Jiang G, Hong Z, Chen Q, Yang M, He S, Liu S, Chen J, Li K, Li X, Liao J, Chen J, Chen S. Crystal Structures of Bat and Human Coronavirus ORF8 Protein Ig-Like Domain Provide Insights Into the Diversity of Immune Responses. Front Immunol 2021;12:807134.
  31. Flower TG, Buffalo CZ, Hooy RM, Allaire M, Ren X, Hurley JH. Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein. Proc Natl Acad Sci U S A 2021;118:e2021785118.
  32. Assadizadeh M, Azimzadeh Irani M. Oligomer formation of SARS-CoV-2 ORF8 through 73YIDI76 motifs regulates immune response and non-infusion antiviral interactions. Front Mol Biosci 2023;10:1270511.
  33. 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;30:269-271.
  34. Trial Consortium WS, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernandez Garcia C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Periago MR, Hanna PA, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, Garcia PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hotton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manel O, McGinty S, Medina MT, Rubio MLM, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portoles A, Rasmin MR, Raza A, Rees H, Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen KAO, Trelle S, Zaid H, Rottingen JA, Swaminathan S. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med 2021;384:497-511.
  35. Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov Today 2016;21:204-207.
  36. Chakravarti R, Singh R, Ghosh A, Dey D, Sharma P, Velayutham R, Roy S, Ghosh D. A review on potential of natural products in the management of COVID-19. RSC Adv 2021;11:16711-16735.
  37. Christy MP, Uekusa Y, Gerwick L, Gerwick WH. Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2. J Nat Prod 2021;84:161-182.
  38. Llivisaca-Contreras SA, Naranjo-Morán J, Pino-Acosta A, Pieters L, Vanden Berghe W, Manzano P, Vargas-Perez J, Leon-Tamariz F, Cevallos-Cevallos JM. Plants and Natural Products with Activity against Various Types of Coronaviruses: A Review with Focus on SARS-CoV-2. Molecules 2021;26:4099.
  39. Atanasov AG, Zotchev SB, Dirsch VM, International Natural Product Sciences Taskforce, Supuran CT. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 2021;20:200-216.
  40. McChesney JD. Natural products in drug discovery--organizing for success. P R Health Sci J 2002;21:91-95.
  41. Yang J, Zhang Y. Protein structure and function prediction using I-TASSER. Curr Protoc Bioinformatics 2015;52:5.8.1-5.815.
  42. Zhou Y, Gilmore K, Ramirez S, Settels E, Gammeltoft KA, Pham LV, Fahnøe U, Feng S, Offersgaard A, Trimpert J, Bukh J, Osterrieder K, Gottwein JM, Seeberger PH. In vitro efficacy of artemisinin-based treatments against SARS-CoV-2. Sci Rep 2021;11:14571.
  43. Mannan A, Ahmed I, Arshad W, Asim MF, Qureshi RA, Hussain I, Mirza B. Survey of artemisinin production by diverse Artemisia species in northern Pakistan. Malar J 2010;9: 310.
  44. Siadat S, Direkvand-Moghadam F. Study of phytochemical characteristics Artemisia persica Boiss in Ilam Province. Future Natural Products 2018;4(3):55-63.
  45. Shandilya A, Chacko S, Jayaram B, Ghosh I. A plausible mechanism for the antimalarial activity of artemisinin: A computational approach. Sci Rep 2013;3:2513.
  46. Wang J, Xu C, Wong YK, Li Y, Liao F, Jiang T, Tu Y. Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine. Proc Est Acad Sci Eng 2019;5:32-39.
  47. Tilley L, Straimer J, Gnädig NF, Ralph SA, Fidock DA. Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol 2016;32:682-696.
  48. White NJ. Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg 1994;88 Suppl 1:S41-S43.
  49. Li Q, Weina PJ, Milhous WK. Pharmacokinetic and Pharmacodynamic Profiles of Rapid-Acting Artemisinins in the Antimalarial Therapy. Curr Drug ther 2007;2:210-223.
  50. Laing R, Gillan V, Devaney E. Ivermectin - Old Drug, New Tricks?. Trends Parasitol 2017;33:463-472.
  51. Lawrence JM, Meyerowitz-Katz G, Heathers JAJ, Brown NJL, Sheldrick KA. The lesson of ivermectin: meta-analyses based on summary data alone are inherently unreliable. Nat Med 2021;27:1853-1854.
  52. Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, Tham TC. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am J Ther 2021;28:e434-e460.
  53. Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, Phru CS, Rahman M, Zaman K, Somani J, Yasmin R, Hasnat MA, Kabir A, Binte Aziz A, Khan WA. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis 2021;103:214-216.
  54. Yang S, Shen S, Hou N. Is Ivermectin Effective in Treating COVID-19?. Front Pharmacol 2022;13:858693.
  55. Roman YM, Burela PA, Pasupuleti V, Piscoya A, Vidal JE, Hernandez AV. Ivermectin for the Treatment of Coronavirus Disease 2019: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Infect Dis 2022;74:1022-1029.
  56. Biber A, Harmelin G, Lev D, Ram L, Shaham A, Nemet I, Kliker L, Erster O, Mandelboim M, Schwartz E. The effect of ivermectin on the viral load and culture viability in early treatment of nonhospitalized patients with mild COVID-19 - a double-blind, randomized placebo-controlled trial. Int J Infect Dis 2022;122:733-740.
  57. Chaccour C, Hammann F, Rabinovich NR. Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety. Malar J 2017;16:161.
  58. Peña-Silva R, Duffull SB, Steer AC, Jaramillo-Rincon SX, Gwee A, Zhu X. Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19. Br J Clin Pharmacol 2021;87:1589-1590.
  59. Camby I, Le Mercier M, Lefranc F, Kiss R. Galectin-1: a small protein with major functions. Glycobiology 2006;16:137R-157R.
  60. Giguère D, Bonin M-A, Cloutier P, Patnam R, St-Pierre C, Sato S, Roy R. Synthesis of stable and selective inhibitors of human galectins-1 and -3. Bioorg Med Chem. 2008;16:7811-7823.
  61. Benson DA, Cavanaugh M, Clark K, Karsch-Mizrachi I, Lipman DJ, Ostell J, Sayers EW. GenBank. Nucleic Acids Res. 2013;41: D36-42.
  62. Berman HM, Battistuz T, Bhat TN, Bluhm WF, Bourne PE, Burkhardt K, Feng Z, Gilliland GL, Iype L, Jain S, Fagan P, Marvin J, Padilla D, Ravichandran V, Schneider B, Thanki N, Weissig H, Westbrook JD, Zardecki C. The Protein Data Bank. Acta Crystallogr D Biol Crystallogr 2002;58(Pt 6 No 1):899-907.
  63. Fiser A, Sali A. ModLoop: automated modeling of loops in protein structures. Bioinformatics 2003;19:2500-2501.
  64. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605-1612.
  65. Schlick T. Molecular modeling and simulation: an interdisciplinary guide. 2010. Available: https://link.springer.com/book/10.1007/978-0-387-22464-0
  66. Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, Zaslavsky L, Zhang J, Bolton EE. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res 2019;47:D1102-D1109.
  67. Kerwin SM. ChemBioOffice Ultra 2010 Suite. J Am Chem Soc 2010;132:2466-2467.
  68. Dyshlovenko PE. Adaptive numerical method for Poisson–Boltzmann equation and its application. Comput Phys Commun 2002;147:335-338.
  69. Roy A, Kucukural A, Zhang Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 2010;5:725-738.
  70. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 2008;9:40.
  71. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004;32:1792-1797.
  72. Clamp M, Cuff J, Searle SM, Barton GJ. The Jalview Java alignment editor. Bioinformatics 2004;20:426-427.
  73. Waterhouse AM, Procter JB, Martin DMA, Clamp M, Barton GJ. Jalview Version 2--a multiple sequence alignment editor and analysis workbench. Bioinformatics 2009;25:1189-1191.
  74. Saha D, Patgaonkar M, Shroff A, Ayyar K, Bashir T, Reddy KVR. Hemoglobin expression in nonerythroid cells: novel or ubiquitous?. Int J Inflam 2014;2014:803237.
  75. Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract 2020;10:1271.
  76. Nitsure M, Sarangi B, Shankar GH, Reddy VS, Walimbe A, Sharma V, Prayag S. Mechanisms of Hypoxia in COVID-19 Patients: A Pathophysiologic Reflection. Indian J Crit Care Med 2020;24:967-970.
  77. Wunsch H. Mechanical Ventilation in COVID-19: Interpreting the Current Epidemiology. Am J Respir Crit Care Med 2020;202:1-4.
  78. Egbert M, Whitty A, Keserű GM, Vajda S. Why Some Targets Benefit from beyond Rule of Five Drugs. J Med Chem 2019;62:10005-10025.
  79. Doak BC, Kihlberg J. Drug discovery beyond the rule of 5 - Opportunities and challenges. Expert Opin Drug Discov 2017;12:115-119.
  80. Villar EA, Beglov D, Chennamadhavuni S, Porco Jr JA, Kozakov D, Vajda S, Whitty A. How proteins bind macrocycles. Nat Chem Biol 2014;10:723-731.
  81. Surade S, Blundell TL. Structural biology and drug discovery of difficult targets: the limits of ligandability. Chem Biol 2012;19:42-50.
  82. Krieger J, Smeilus T, Kaiser M, Seo EJ, Efferth T, Giannis A. Total synthesis and biological investigation of (-)-artemisinin: The antimalarial activity of artemisinin is not stereospecific. Angew Chem Int Ed Engl 2018;57:8293-8296.
  83. Fourmont L, Revest M, Polard E, Lederlin M, Delaval P, Desrues B, Tattevin P, Jouneau S. Acute eosinophilic pneumonia following artenimol–piperaquine exposure. J Travel Med 2017;24.
  84. Campbell WC. History of Avermectin and Ivermectin, with Notes on the History of Other Macrocyclic Lactone Antiparasitic Agents. Curr Pharm Biotechnol 2012;13:853-865.
  85. Shoop W, Soll M. Chemistry, pharmacology and safety of the macrocyclic lactones: ivermectin, abamectin and eprinomectin. Macrocyclic lactones in antiparasitic therapy. UK: CAB International; 2002. pp.1-29.
  86. St-Pierre C, Ouellet M, Giguère D, Ohtake R, Roy R, Sato S, Tremblay MJ. Galectin-1-specific inhibitors as a new class of compounds to treat HIV-1 infection. Antimicrob Agents Chemother 2012;56:154-162.
  87. Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci 2020;253:117592.
  88. Gandhi S, Klein J, Robertson AJ, Peña-Hernández MA, Lin MJ, Roychoudhury P, Lu P, Fournier J, Ferguson D, Shah AK, Bakhash M, Muenker MC, Srivathsan A, Wunder Jr EA, Kerantzas N, Wang W, Lindenbach B, Pyle A, Wilen CB, Ogbuagu O, Greninger AL, Iwasaki A, Schulz WL, Ko AI. De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report. Nat  Commun 2022;13:1547.
  89. Humeniuk R, Mathias A, Kirby BJ, Lutz JD, Cao H, Osinusi A, Babusis D, Porter D, Wei X, Ling J, Reddy YS, German P. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor. Clin Pharmacokinet 2021;60: 569-583.
  90. Huey R, Morris GM, Forli S, Others. Using AutoDock 4 and AutoDock vina with AutoDockTools: a tutorial. The Scripps Research Institute Molecular Graphics Laboratory. 2012;10550: 1000.
  91. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31: 455-461.
  92. Hetényi C, van der Spoel D. Toward prediction of functional protein pockets using blind docking and pocket search algorithms. Protein Sci 2011;20:880-893.
  93. Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res 2015;43(W1):W443-W447.
  94. Adasme MF, Linnemann KL, Bolz SN, Kaiser F, Salentin S, Haupt VJ, Schroeder M. PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA. Nucleic Acids Res 2021;49:W530-W534.
  95. C SLL. The PyMOL molecular graphics system. Version 2015;1: 8. Available: https://cir.nii.ac.jp/crid/1370294643858081026.
  96. Ziegel ER, Berk KN, Carey P. Data Analysis with Microsoft® Excel. Technometrics 1999;41:380.
  97. Chaudhari AM, Singh I, Joshi M, Patel A, Joshi C. Defective ORF8 dimerization in SARS-CoV-2 delta variant leads to a better adaptive immune response due to abrogation of ORF8-MHC1 interaction. Mol Divers 2023;27:45-57.
  98. Matsuoka K, Imahashi N, Ohno M, Ode H, Nakata Y, Kubota M, Sugimoto A, Imahashi M, Yokomaku Y, Iwatani Y. SARS-CoV-2 accessory protein ORF8 is secreted extracellularly as a glycoprotein homodimer. J Biol Chem 2022;298:101724.
  99. Pereira F. Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene. Infect Genet Evol 2020;85:104525.
  100. Alkhansa A, Lakkis G, El Zein L. Mutational analysis of SARS-CoV-2 ORF8 during six months of COVID-19 pandemic. Gene Rep 2021;23:101024. 

Files

Share

How to cite

Statistics