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Zhu C, Pang S, Liu J, Duan Q. Current Progress, Challenges and prospects in the development of COVID-19 vaccines. Drugs. 2024; 84:403-423.","DOI":"10.1007\/s40265-024-02013-8"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2. Kaku Y, Uriu K, Kosugi Y, Okumura K, Yamasoba D, Uwamino Y, Kuramochi J, Sadamasu K, Yoshimura K, Asakura H, Nagashima M, Ito J, Sato K. Virological characteristics of the SARS-CoV-2 KP.2 variant. Lancet Infect Dis. 2024; 24:e416.","DOI":"10.1016\/S1473-3099(24)00298-6"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3. Yang H, Rao Z. Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat Rev Microbiol. 2021; 19:685-700.","DOI":"10.1038\/s41579-021-00630-8"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4. Shin D, Mukherjee R, Grewe D, <i>et al<\/i>. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature. 2020; 587:657-662.","DOI":"10.1038\/s41586-020-2601-5"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5. Proti\u0107 S, Crnoglavac Popovi\u0107 M, Kali\u010danin N, Prodanovi\u0107 O, Sen\u0107anski M, Mili\u0107evi\u0107 J, Stevanovi\u0107 K, Perovi\u0107 V, Paessler S, Prodanovi\u0107 R, Gli\u0161i\u0107 S. SARS-CoV-2 PLpro inhibition: evaluating <i>in silico<\/i> repurposed fidaxomicin&apos;s antiviral activity through <i>in vitro<\/i> assessment. ChemistryOpen. 2024; 13:e202400091.","DOI":"10.1002\/open.202400091"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Freitas BT, Durie IA, Murray J, Longo JE, Miller HC, Crich D, Hogan RJ, Tripp RA, Pegan SD. Characterization and noncovalent inhibition of the deubiquitinase and deISGylase activity of SARS-CoV-2 papain-like protease. ACS Infect Dis. 2020; 6:2099-2109.","DOI":"10.1021\/acsinfecdis.0c00168"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. Shen Z, Ratia K, Cooper L, Kong D, Lee H, Kwon Y, Li Y, Alqarni S, Huang F, Dubrovskyi O, Rong L, Thatcher G, Xiong R. Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity. J Med Chem. 2022; 65:2940-2955.","DOI":"10.1021\/acs.jmedchem.1c01307"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8. Tan B, Zhang X, Ansari A, Jadhav P, Tan H, Li K, Chopra A, Ford A, Chi X, Ruiz FX, Arnold E, Deng X, Wang J. Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model. Science. 2024; 383:1434-1440.","DOI":"10.1126\/science.adm9724"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9. Xu Y, Chen K, Pan J, Lei Y, Zhang D, Fang L, Tang J, Chen X, Ma Y, Zheng Y, Zhang B, Zhou Y, Zhan J, Xu W. Repurposing clinically approved drugs for COVID-19 treatment targeting SARS-CoV-2 papain-like protease. Int J Biol Macromol. 2021; 188:137-146.","DOI":"10.1016\/j.ijbiomac.2021.07.184"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10. Cho CC, Li SG, Lalonde TJ, Yang KS, Yu G, Qiao Y, Xu S, Ray Liu W. Drug repurposing for the SARS-CoV-2 papain-like protease. ChemMedChem. 2022; 17:e202100455.","DOI":"10.1002\/cmdc.202200053"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11. Srinivasan V, Brognaro H, Prabhu PR, <i>et al<\/i>. Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease. Commun Biol. 2022; 5:805.","DOI":"10.1038\/s42003-022-03737-7"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12. Zhao Y, Du X, Duan Y, <i>et al.<\/i> High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors. Protein Cell. 2021; 12:877-888.","DOI":"10.1007\/s13238-021-00836-9"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13. Weglarz-Tomczak E, Tomczak JM, Talma M, Burda-Grabowska M, Giurg M, Brul S. Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2. Sci Rep. 2021; 11:3640.","DOI":"10.1038\/s41598-021-83229-6"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14. Sargsyan K, Lin CC, Chen T, Grauffel C, Chen YP, Yang WZ, Yuan HS, Lim C. Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors. Chem Sci. 2020; 11:9904-9909.","DOI":"10.1039\/D0SC02646H"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15. Yi Y, Zhang M, Xue H, <i>et al.<\/i> Schaftoside inhibits 3CLpro and PLpro of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19. Acta Pharm Sin B. 2022; 12:4154-4164.","DOI":"10.1016\/j.apsb.2022.07.017"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16. Kuo CJ, Chao TL, Kao HC, Tsai YM, Liu YK, Wang LH, Hsieh MC, Chang SY, Liang PH. Kinetic characterization and inhibitor screening for the proteases leading to identification of drugs against SARS-CoV-2. Antimicrob Agents Chemother. 2021; 65:e02577-20.","DOI":"10.1128\/AAC.02577-20"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17. Yu W, Zhao Y, Ye H, Wu N, Liao Y, Chen N, Li Z, Wan N, Hao H, Yan H, Xiao Y, Lai M. Structure-Based Design of a Dual-Targeted Covalent Inhibitor Against Papain-like and Main Proteases of SARS-CoV-2. J Med Chem. 2022; 65:16252-16267.","DOI":"10.1021\/acs.jmedchem.2c00954"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18. Rut W, Lv Z, Zmudzinski M, Patchett S, Nayak D, Snipas SJ, El Oualid F, Huang TT, Bekes M, Drag M, Olsen SK. Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: a framework for anti-COVID-19 drug design. Sci Adv. 2020; 6:eabd4596.","DOI":"10.1126\/sciadv.abd4596"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19. Li Y, Li L, Wang S, Tang X. EQUIBIND: A geometric deep learning-based protein-ligand binding prediction method. Drug Discov Ther. 2023; 17:363-364.","DOI":"10.5582\/ddt.2023.01063"},{"key":"20","unstructured":"20. Boby ML, Fearon D, Ferla M, <i>et al<\/i>. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. Science. 2023; 382:eabo7201."},{"key":"21","unstructured":"21. Garnsey MR, Robinson MC, Nguyen LT, <i>et al.<\/i> Discovery of SARS-CoV-2 papain-like protease (PLpro) inhibitors with efficacy in a murine infection model. Sci Adv. 2024; 10:eado4288."},{"key":"22","doi-asserted-by":"crossref","unstructured":"22. Zhao J, Shi X, Wang Z, Xiong S, Lin Y, Wei X, Li Y, Tang X. Hepatotoxicity assessment investigations on PFASs targeting L-FABP using binding affinity data and machine learning-based QSAR model. Ecotoxicol Environ Saf. 2023; 262:115310.","DOI":"10.1016\/j.ecoenv.2023.115310"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23. Wei X, Liu N, Feng Y, Wang H, Han W, Zhuang M, Zhang H, Gao W, Lin Y, Tang X, Zheng Y. Competitive-like binding between carbon black and CTNNB1 to \u0394Np63 interpreting the abnormal respiratory epithelial repair after injury. Sci Total Environ. 2024; 929:172652.","DOI":"10.1016\/j.scitotenv.2024.172652"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24. Hu H, Wang Q, Su H, Shao Q, Zhao W, Chen G, Li M, Xu Y. Identification of cysteine 270 as a novel site for allosteric modulators of SARS-CoV-2 papain-like protease. Angew Chem. 2022; 61:e202212378.","DOI":"10.1002\/anie.202212378"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25. Li Y, Wang Z, Ma S, Tang X, Zhang H. Chemical space exploration and machine learning-based screening of PDE7A inhibitors. Pharmaceuticals. 2025; 18:444","DOI":"10.3390\/ph18040444"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26. 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.","DOI":"10.1002\/jcc.21334"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T, Caldwell J, Wang J, Kollman P. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem. 2003; 24:1999-2012.","DOI":"10.1002\/jcc.10349"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983; 79:926-935.","DOI":"10.1063\/1.445869"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29. Bayly CI, Cieplak P, Cornell W, Kollman PA. A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J Phys Chem. 1993; 97:10269-10280.","DOI":"10.1021\/j100142a004"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30. Ryckaert J-P, Ciccotti G, Berendsen HJC. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys. 1977; 23:327-341.","DOI":"10.1016\/0021-9991(77)90098-5"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31. Genheden S, Ryde U. The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov. 2015; 10:449-461.","DOI":"10.1517\/17460441.2015.1032936"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32. Velma GR, Shen Z, Holberg C, <i>et al.<\/i> Non-covalent inhibitors of SARS-CoV-2 papain-like protease (PLpro): <i>in vitro<\/i> and <i>in vivo<\/i> antiviral activity. J Med Chem. 2024; 67:13681-13702.","DOI":"10.1021\/acs.jmedchem.4c00378"},{"key":"33","unstructured":"33. Garnsey MR, Robinson MC, Nguyen LT, <i>et al.<\/i> Discovery of SARS-CoV-2 papain-like protease (PLpro) inhibitors with efficacy in a murine infection model. Sci Adv. 2024; 10:eado4288."},{"key":"34","doi-asserted-by":"crossref","unstructured":"34. Zmudzinski M, Rut W, Olech K, <i>et al.<\/i> Ebselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins: PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase. Sci Rep. 2023; 13:9161.","DOI":"10.1038\/s41598-023-35907-w"},{"key":"35","doi-asserted-by":"crossref","unstructured":"35. Hu H, Wang Q, Su H, Shao Q, Zhao W, Chen G, Li M, Xu Y. 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