Identification and evaluation of antiviral activity of novel compounds targeting SARS-CoV-2 virus by enzymatic and antiviral assays, and computational analysis

References

• Corman VM, Lienau J, Witzenrath M. Coronaviruses as the cause of respiratory infections. Internist (Berl)). 2019;60(11):1136–1145.
   PubMed Web of Science ®Google Scholar
• Fehr AR, Channappanavar R, Perlman S. Middle east respiratory syndrome: Emergence of a pathogenic human coronavirus. Annu Rev Med. 2017;68(1):387–399.
   PubMedGoogle Scholar
• Volz E, Hill V, McCrone JT, Price A, Jorgensen D, O'Toole A, Southgate J, Johnson R, Jackson B, Nascimento FF, et al. Evaluating the effects of sars-cov-2 spike mutation d614g on transmissibility and pathogenicity. Cell. 2021;184(1):64–75 e11.
   PubMed Web of Science ®Google Scholar
• Saputri DS, Li S, van Eerden FJ, Rozewicki J, Xu Z, Ismanto HS, Davila A, Teraguchi S, Katoh K, Standley DM. Flexible, functional, and familiar: Characteristics of sars-cov-2 spike protein evolution. Front Microbiol. 2020;11:2112.
   PubMed Web of Science ®Google Scholar
• Khateeb J, Li Y, Zhang H. Emerging sars-cov-2 variants of concern and potential intervention approaches. Crit Care. 2021;25(1):244.
   PubMed Web of Science ®Google Scholar
• Cohen J. Omicron sparks a vaccine strategy debate. Science. 2021;374(6575):1544–1545.
   Web of Science ®Google Scholar
• Nepali K, Sharma R, Sharma S, Thakur A, Liou JP. Beyond the vaccines: A glance at the small molecule and peptide-based anti-covid19 arsenal. J Biomed Sci. 2022;29(1):65.
   Web of Science ®Google Scholar
• Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut N, Morin MJ, Szewczyk LJ, Painter GR. Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against sars-cov-2. Antimicrob Agents Chemother. 2021;65(5):e02428–02420.
   PubMed Web of Science ®Google Scholar
• Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ, et al. An oral sars-cov-2 m(pro) inhibitor clinical candidate for the treatment of covid-19. Science. 2021;374(6575):1586–1593.
   PubMed Web of Science ®Google Scholar
• Ulrich L, Halwe NJ, Taddeo A, Ebert N, Schön J, Devisme C, Trüeb BS, Hoffmann B, Wider M, Fan X, et al. Enhanced fitness of sars-cov-2 variant of concern alpha but not beta. Nature. 2022;602(7896):307–313.
   Web of Science ®Google Scholar
• Moghadasi SA, Heilmann E, Khalil AM, Nnabuife C, Kearns FL, Ye C, Moraes SN, Costacurta F, Esler MA, Aihara H, et al. Transmissible sars-cov-2 variants with resistance to clinical protease inhibitors. Sci Adv. 2023;9(13):eade8778.
   PubMed Web of Science ®Google Scholar
• Vangeel L, Chiu W, De Jonghe S, Maes P, Slechten B, Raymenants J, André E, Leyssen P, Neyts J, Jochmans D. Remdesivir, molnupiravir and nirmatrelvir remain active against sars-cov-2 omicron and other variants of concern. Antiviral Res. 105252;198:105252.
   Web of Science ®Google Scholar
• Shin D, Mukherjee R, Grewe D, Bojkova D, Baek K, Bhattacharya A, Schulz L, Widera M, Mehdipour AR, Tascher G, et al. Papain-like protease regulates sars-cov-2 viral spread and innate immunity. Nature. 2020;587(7835):657–662.
   PubMed Web of Science ®Google Scholar
• Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-ncov). Nat Rev Drug Discov. 2020;19(3):149–150.
   PubMed Web of Science ®Google Scholar
• Xia S, Liu M, Wang C, Xu W, Lan Q, Feng S, Qi F, Bao L, Du L, Liu S, et al. Inhibition of sars-cov-2 (previously 2019-ncov) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res. 2020;30(4):343–355.
   PubMed Web of Science ®Google Scholar
• Marzolini C, Kuritzkes DR, Marra F, Boyle A, Gibbons S, Flexner C, Pozniak A, Boffito M, Waters L, Burger D, et al. Recommendations for the management of drug-drug interactions between the covid-19 antiviral nirmatrelvir/ritonavir (paxlovid) and comedications. Clin Pharmacol Ther. 2022;112(6):1191–1200.
   PubMed Web of Science ®Google Scholar
• Lamb YN. Nirmatrelvir plus ritonavir: First approval. Drugs. 2022;82(5):585–591.
   PubMed Web of Science ®Google Scholar
• Iketani S, Mohri H, Culbertson B, Hong SJ, Duan Y, Luck MI, Annavajhala MK, Guo Y, Sheng Z, Uhlemann AC, et al. Multiple pathways for sars-cov-2 resistance to nirmatrelvir. Nature. 2023;613(7944):558–564.
   PubMed Web of Science ®Google Scholar
• Hu Y, Lewandowski EM, Tan H, Zhang X, Morgan RT, Zhang X, Jacobs LMC, Butler SG, Gongora MV, Choy J, et al. Naturally occurring mutations of sars-cov-2 main protease confer drug resistance to nirmatrelvir. ACS Cent Sci. 2023;9(8):1658–1669.
   PubMedGoogle Scholar
• Ullrich S, Sasi VM, Mahawaththa MC, Ekanayake KB, Morewood R, George J, Shuttleworth L, Zhang X, Whitefield C, Otting G, et al. Challenges of short substrate analogues as sars-cov-2 main protease inhibitors. Bioorg Med Chem Lett. 2021;50(:128333.
   Web of Science ®Google Scholar
• Klemm T, Ebert G, Calleja DJ, Allison CC, Richardson LW, Bernardini JP, Lu BG, Kuchel NW, Grohmann C, Shibata Y, et al. Mechanism and inhibition of the papain-like protease, plpro, of sars-cov-2. Embo J. 2020;39(18):e106275.
   PubMed Web of Science ®Google Scholar
• Rut W, Lv Z, Zmudzinski M, Patchett S, Nayak D, Snipas SJ, El Oualid F, Huang TT, Bekes M, Drag M, et al. 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(42):eabd4596.
   PubMed Web of Science ®Google Scholar
• 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(8):2099–2109.
   PubMed Web of Science ®Google Scholar
• Sulea T, Lindner HA, Purisima EO, Ménard R. Deubiquitination, a new function of the severe acute respiratory syndrome coronavirus papain-like protease? J Virol. 2005;79(7):4550–4551.
   PubMed Web of Science ®Google Scholar
• Báez-Santos YM, St John SE, Mesecar AD. The sars-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds. Antiviral Res. 2015;115(:21–38.
   PubMed Web of Science ®Google Scholar
• Balakirev MY, Jaquinod M, Haas AL, Chroboczek J. Deubiquitinating function of adenovirus proteinase. J Virol. 2002;76(12):6323–6331.
   Web of Science ®Google Scholar
• Shen Z, Ratia K, Cooper L, Kong D, Lee H, Kwon Y, Li Y, Alqarni S, Huang F, Dubrovskyi O, et al. Design of sars-cov-2 plpro inhibitors for covid-19 antiviral therapy leveraging binding cooperativity. J Med Chem. 2022;65(4):2940–2955.
   Web of Science ®Google Scholar
• Calleja DJ, Lessene G, Komander D. Inhibitors of sars-cov-2 plpro. Front Chem. 2022;10:876212.
   PubMed Web of Science ®Google Scholar
• Tan H, Hu Y, Jadhav P, Tan B, Wang J. Progress and challenges in targeting the sars-cov-2 papain-like protease. J Med Chem. 2022;65(11):7561–7580.
   PubMed Web of Science ®Google Scholar
• Bazzaro M, Linder S. Dienone compounds: Targets and pharmacological responses. J Med Chem. 2020;63(24):15075–15093.
   Web of Science ®Google Scholar
• Das U, Sharma RK, Dimmock JR. 1,5-diaryl-3-oxo-1,4-pentadienes: A case for antineoplastics with multiple targets. Curr Med Chem. 2009;16(16):2001–2020.
   Web of Science ®Google Scholar
• Cersosimo U, Sgorbissa A, Foti C, Drioli S, Angelica R, Tomasella A, Picco R, Semrau MS, Storici P, Benedetti F, et al. Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent. J Med Chem. 2015;58(4):1691–1704.
   Web of Science ®Google Scholar
• Tomasella A, Picco R, Ciotti S, Sgorbissa A, Bianchi E, Manfredini R, Benedetti F, Trimarco V, Frezzato F, Trentin L, et al. The isopeptidase inhibitor 2cpe triggers proteotoxic stress and atm activation in chronic lymphocytic leukemia cells. Oncotarget. 2016;7(29):45429–45443.
   Google Scholar
• Iuliano L, Drioli S, Pignochino Y, Cafiero CM, Minisini M, D'Este F, Picco R, Dalla E, Giordano G, Grignani G, et al. Enhancing proteotoxic stress in leiomyosarcoma cells triggers mitochondrial dysfunctions, cell death, and antitumor activity in vivo. Mol Cancer Ther. 2021;20(6):1039–1051.
   Web of Science ®Google Scholar
• Ciotti S, Sgarra R, Sgorbissa A, Penzo C, Tomasella A, Casarsa F, Benedetti F, Berti F, Manfioletti G, Brancolini C. The binding landscape of a partially-selective isopeptidase inhibitor with potent pro-death activity, based on the bis(arylidene)cyclohexanone scaffold. Cell Death Dis. 2018;9(2):184.
   Google Scholar
• Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. Coronavirus main proteinase (3clpro) structure: Basis for design of anti-sars drugs. Science. 2003;300(5626):1763–1767.
   PubMed Web of Science ®Google Scholar
• Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F, et al. Structure-based design of antiviral drug candidates targeting the sars-cov-2 main protease. Science. 2020;368(6497):1331–1335.
   PubMed Web of Science ®Google Scholar
• Jin W, Zhang W, Mitra D, McCandless MG, Sharma P, Tandon R, Zhang F, Linhardt RJ. The structure-activity relationship of the interactions of sars-cov-2 spike glycoproteins with glucuronomannan and sulfated galactofucan from saccharina japonica. Int J Biol Macromol. 2020;163:1649–1658.
   Web of Science ®Google Scholar
• Li J, Zhou X, Zhang Y, Zhong F, Lin C, McCormick PJ, Jiang F, Luo J, Zhou H, Wang Q, et al. Crystal structure of sars-cov-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode. Sci Bull (Beijing). 2021;66(7):661–663.
   PubMed Web of Science ®Google Scholar
• Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of sars-cov-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors. Science. 2020;368(6489):409–412.
   PubMed Web of Science ®Google Scholar
• Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, Maruyama Y, Taoda Y, Kasamatsu K, Suto T, et al. Discovery of s-217622, a noncovalent oral sars-cov-2 3cl protease inhibitor clinical candidate for treating covid-19. J Med Chem. 2022;65(9):6499–6512.
   PubMed Web of Science ®Google Scholar
• Sharma A, Kaliya K, Maurya SK. Recent advances in the discovery of potent proteases inhibitors targeting the sars coronaviruses. Curr Top Med Chem. 2021;21(4):307–328.
   Web of Science ®Google Scholar
• Su H, Zhou F, Huang Z, Ma X, Natarajan K, Zhang M, Huang Y, Su H. Molecular insights into small-molecule drug discovery for sars-cov-2. Angew Chem Int Ed Engl. 2021;60(18):9789–9802.
   Web of Science ®Google Scholar
• Sung H, Kang SH, Bae YJ, Hong JT, Chung YB, Lee CK, Song S. Pcr-based detection of mycoplasma species. J Microbiol. 2006;44(1):42–49.
   Web of Science ®Google Scholar
• Ogawa M, Uchiyama T, Satoh M, Ando S. Decontamination of mycoplasma-contaminated orientia tsutsugamushi strains by repeating passages through cell cultures with antibiotics. BMC Microbiol. 2013;13(1):32.
   Google Scholar
• 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(1):e202100455.
   PubMed Web of Science ®Google Scholar
• Cowell IG, Ling EM, Swan RL, Brooks MLW, Austin CA. The deubiquitinating enzyme inhibitor pr-619 is a potent DNA topoisomerase ii poison. Mol Pharmacol. 2019;96(5):562–572.
   Web of Science ®Google Scholar
• Fu Z, Huang B, Tang J, Liu S, Liu M, Ye Y, Liu Z, Xiong Y, Zhu W, Cao D, et al. The complex structure of grl0617 and sars-cov-2 plpro reveals a hot spot for antiviral drug discovery. Nat Commun. 2021;12(1):488.
   PubMed Web of Science ®Google Scholar
• Hu Y, Ma C, Szeto T, Hurst B, Tarbet B, Wang J. Boceprevir, calpain inhibitors ii and xii, and gc-376 have broad-spectrum antiviral activity against coronaviruses. ACS Infect Dis. 2021;7(3):586–597.
   PubMed Web of Science ®Google Scholar
• Ma C, Sacco MD, Hurst B, Townsend JA, Hu Y, Szeto T, Zhang X, Tarbet B, Marty MT, Chen Y, et al. Boceprevir, gc-376, and calpain inhibitors ii, xii inhibit sars-cov-2 viral replication by targeting the viral main protease. Cell Res. 2020;30(8):678–692.
   PubMed Web of Science ®Google Scholar
• Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, et al. Coronavirus susceptibility to the antiviral remdesivir (gs-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2):e00221–00218.
   PubMed Web of Science ®Google Scholar
• Pruijssers AJ, George AS, Schäfer A, Leist SR, Gralinksi LE, Dinnon KH, Yount BL, Agostini ML, Stevens LJ, Chappell JD, et al. Remdesivir inhibits sars-cov-2 in human lung cells and chimeric sars-cov expressing the sars-cov-2 rna polymerase in mice. Cell Rep. 2020;32(3):107940.
   PubMed Web of Science ®Google Scholar
• Wang J, Reiss K, Shi Y, Lolis E, Lisi GP, Batista VS. Mechanism of inhibition of the reproduction of sars-cov-2 and ebola viruses by remdesivir. Biochemistry. 2021;60(24):1869–1875.
   Web of Science ®Google Scholar
• 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(3):269–271.
   PubMed Web of Science ®Google Scholar
• Zupin L, Fontana F, Gratton R, Milani M, Clemente L, Pascolo L, Ruscio M, Crovella S. Sars-cov-2 short-time infection produces relevant cytopathic effects in vero e6 cell line. Int J Environ Res Public Health. 2021; 18(17):9020–9027.
   Web of Science ®Google Scholar
• Hidalgo IJ, Raub TJ, Borchardt RT. Characterization of the human colon carcinoma cell line (caco-2) as a model system for intestinal epithelial permeability. Gastroenterology. 1989;96(2):736–749.
   PubMedGoogle Scholar
• Zheng G, Li LF, Zhang Y, Qu L, Wang W, Li M, Yu S, Zhou M, Luo Y, Sun Y, et al. Mertk is a host factor that promotes classical swine fever virus entry and antagonizes innate immune response in pk-15 cells. Emerg Microbes Infect. 2020;9(1):571–581.
   PubMed Web of Science ®Google Scholar
• Foster KA, Oster CG, Mayer MM, Avery ML, Audus KL. Characterization of the a549 cell line as a type ii pulmonary epithelial cell model for drug metabolism. Exp Cell Res. 1998;243(2):359–366.
   PubMed Web of Science ®Google Scholar
• De Madrid AT, Porterfield JS. A simple micro-culture method for the study of group b arboviruses. Bull World Health Organ. 1969;40(1):113–121.
   Web of Science ®Google Scholar
• Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1-2):55–63.
   PubMed Web of Science ®Google Scholar
• Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The protein data bank. Nucleic Acids Res. 2000;28(1):235–242.
   PubMed Web of Science ®Google Scholar
• Gao X, Qin B, Chen P, Zhu K, Hou P, Wojdyla JA, Wang M, Cui S. Crystal structure of sars-cov-2 papain-like protease. Acta Pharm Sin B. 2021;11(1):237–245.
   PubMed Web of Science ®Google Scholar
• Sanders BC, Pokhrel S, Labbe AD, Mathews II, Cooper CJ, Davidson RB, Phillips G, Weiss KL, Zhang Q, O'Neill H, et al. Potent and selective covalent inhibition of the papain-like protease from sars-cov-2. Nat Commun. 2023;14(1):1733.
   Web of Science ®Google Scholar
• Sapse AM, Schweitzer BS, Dicker AP, Bertino JR, Frecer V. Ab initio studies of aromatic-aromatic and aromatic-polar interactions in the binding of substrate and inhibitor to dihydrofolate reductase. Int J Pept Protein Res. 1992;39(1):18–23.
   Google Scholar
• Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006;49(21):6177–6196.
   PubMed Web of Science ®Google Scholar
• Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang JY, Wang L, Lupyan D, Dahlgren MK, Knight JL, et al. Opls3: A force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput. 2016;12(1):281–296.
   PubMed Web of Science ®Google Scholar
• Frecer V, Májeková M, Miertuš S. Approximate methods for solvent effect calculations on biomolecules. Journal of Molecular Structure (Theochem). 1989;183(3-4):403–419.
   Google Scholar
• Mulliken DK. The protean hydatid mole; report of a case. Obstet Gynecol. 1955;6(2):219–220.
   Web of Science ®Google Scholar
• Geerlings P, De Proft F, Langenaeker W. Conceptual density functional theory. Chem Rev. 2003;103(5):1793–1873.
   PubMed Web of Science ®Google Scholar
• Anchoori RK, Karanam B, Peng S, Wang JW, Jiang R, Tanno T, Orlowski RZ, Matsui W, Zhao M, Rudek MA, et al. A bis-benzylidine piperidone targeting proteasome ubiquitin receptor rpn13/adrm1 as a therapy for cancer. Cancer Cell. 2013;24(6):791–805.
   Web of Science ®Google Scholar
• Issaenko OA, Amerik AY. Chalcone-based small-molecule inhibitors attenuate malignant phenotype via targeting deubiquitinating enzymes. Cell Cycle. 2012;11(9):1804–1817.
   PubMed Web of Science ®Google Scholar
• Nguyen HL, Thai NQ, Truong DT, Li MS. Remdesivir strongly binds to both rna-dependent rna polymerase and main protease of sars-cov-2: Evidence from molecular simulations. J Phys Chem B. 2020;124(50):11337–11348.
   Web of Science ®Google Scholar
• Lavaud M, Mullard M, Tesfaye R, Amiaud J, Legrand M, Danieau G, Brion R, Morice S, Regnier L, Dupuy M, et al. Overexpression of the ubiquitin specific proteases usp43, usp41, usp27x and usp6 in osteosarcoma cell lines: Inhibition of osteosarcoma tumor growth and lung metastasis development by the usp antagonist pr619. Cells. 2021;10(9):2268–2283.
   Web of Science ®Google Scholar
• Pizzorno A, Padey B, Dubois J, Julien T, Traversier A, Dulière V, Brun P, Lina B, Rosa-Calatrava M, Terrier O. In vitro evaluation of antiviral activity of single and combined repurposable drugs against sars-cov-2. Antiviral Res. 104878;181:104878.
   Web of Science ®Google Scholar
• Fu L, Ye F, Feng Y, Yu F, Wang Q, Wu Y, Zhao C, Sun H, Huang B, Niu P, et al. Both boceprevir and gc376 efficaciously inhibit sars-cov-2 by targeting its main protease. Nat Commun. 2020;11(1):4417.
   PubMed Web of Science ®Google Scholar
• Zhuo L-G, Liao W, Yu Z-X. A frontier molecular orbital theory approach to understanding the mayr equation and to quantifying nucleophilicity and electrophilicity by using homo and lumo energies. Asian J Org Chem. 2012;1(4):336–345.
   Web of Science ®Google Scholar
• Ma CL, Wang J. Validation and invalidation of sars-cov-2 papain-like protease inhibitors. ACS Pharmacol Transl Sci. 2022;5(2):102–109.
   PubMedGoogle Scholar
• Brewitz L, Kamps J, Lukacik P, Strain-Damerell C, Zhao Y, Tumber A, Malla TR, Orville AM, Walsh MA, Schofield CJ. Mass spectrometric assays reveal discrepancies in inhibition profiles for the sars-cov-2 papain-like protease. ChemMedChem. 2022;17(9):e202200016.
   Web of Science ®Google Scholar