{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:18:08Z","timestamp":1785928688263,"version":"3.56.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T00:00:00Z","timestamp":1709769600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T00:00:00Z","timestamp":1709769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1A2C2102262"],"award-info":[{"award-number":["NRF-2020R1A2C2102262"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2021R1A2C2004760"],"award-info":[{"award-number":["NRF-2021R1A2C2004760"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2022R1A6A3A03066467"],"award-info":[{"award-number":["NRF-2022R1A6A3A03066467"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HU21C0053"],"award-info":[{"award-number":["HU21C0053"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has evoked a worldwide pandemic. As the emergence of variants has hampered the neutralization capacity of currently available vaccines, developing effective antiviral therapeutics against SARS-CoV-2 and its variants becomes a significant challenge. The main protease (M<jats:sup>pro<\/jats:sup>) of SARS-CoV-2 has received increased attention as an attractive pharmaceutical target because of its pivotal role in viral replication and proliferation. Here, we generated a de novo M<jats:sup>pro<\/jats:sup>-inhibitor screening platform to evaluate the efficacies of M<jats:sup>pro<\/jats:sup> inhibitors based on M<jats:sup>pro<\/jats:sup> cleavage site-embedded amyloid peptide (MCAP)-coated gold nanoparticles (MCAP-AuNPs). We fabricated MCAPs comprising an amyloid-forming sequence and M<jats:sup>pro<\/jats:sup>-cleavage sequence, mimicking in vivo viral replication process mediated by M<jats:sup>pro<\/jats:sup>. By measuring the proteolytic activity of M<jats:sup>pro<\/jats:sup> and the inhibitory efficacies of various drugs, we confirmed that the MCAP-AuNP-based platform was suitable for rapid screening potential of M<jats:sup>pro<\/jats:sup> inhibitors. These results demonstrated that our MCAP-AuNP-based platform has great potential for discovering M<jats:sup>pro<\/jats:sup> inhibitors and may accelerate the development of therapeutics against COVID-19.<\/jats:p>","DOI":"10.1038\/s41467-024-46296-7","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T20:03:20Z","timestamp":1709841800000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8716-1736","authenticated-orcid":false,"given":"Dongtak","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Gi","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5235-7114","authenticated-orcid":false,"given":"Dongsung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junho","family":"Bang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da Yeon","family":"Cheong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Won","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghwan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungmin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Won","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyudo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Ho","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hye","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3590-2074","authenticated-orcid":false,"given":"Kyo Seon","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7344-6060","authenticated-orcid":false,"given":"Jeong Hoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6447-2862","authenticated-orcid":false,"given":"Dae Sung","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"46296_CR1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41579-020-00459-7","volume":"19","author":"B Hu","year":"2021","unstructured":"Hu, B., Guo, H., Zhou, P. & Shi, Z.-L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 19, 141\u2013154 (2021).","journal-title":"Nat. Rev. Microbiol."},{"key":"46296_CR2","unstructured":"WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) dashboard with vaccination data. [accessed 6 Nov 2023]. Available from: https:\/\/covid19.who.int\/."},{"key":"46296_CR3","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1038\/s41586-022-04690-5","volume":"605","author":"MM DeGrace","year":"2022","unstructured":"DeGrace, M. M. et al. Defining the risk of SARS-CoV-2 variants on immune protection. Nature 605, 640\u2013652 (2022).","journal-title":"Nature"},{"key":"46296_CR4","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.3201\/eid2810.221058","volume":"28","author":"AC Keyel","year":"2022","unstructured":"Keyel, A. C. et al. SARS-CoV-2 vaccine breakthrough by Omicron and Delta variants, New York, USA. Emerg. Infect. Dis. 28, 1990\u20131998 (2022).","journal-title":"Emerg. Infect. Dis."},{"key":"46296_CR5","doi-asserted-by":"crossref","unstructured":"Liu, X.-H. et al. Structures of the SARS-CoV-2 spike glycoprotein and applications for novel drug development. Front. Pharmacol. 13, 955648 (2022).","DOI":"10.3389\/fphar.2022.955648"},{"key":"46296_CR6","doi-asserted-by":"publisher","first-page":"12359","DOI":"10.1021\/acs.jmedchem.0c00606","volume":"63","author":"C Gil","year":"2020","unstructured":"Gil, C. et al. COVID-19: drug targets and potential treatments. J. Med. Chem. 63, 12359\u201312386 (2020).","journal-title":"J. Med. Chem."},{"key":"46296_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12929-022-00852-9","volume":"29","author":"M Kumari","year":"2022","unstructured":"Kumari, M. et al. A critical overview of current progress for COVID-19: development of vaccines, antiviral drugs, and therapeutic antibodies. J. Biomed. Sci. 29, 1\u201336 (2022).","journal-title":"J. Biomed. Sci."},{"key":"46296_CR8","first-page":"18","volume":"8","author":"F Barkas","year":"2021","unstructured":"Barkas, F., Styla, C.-P., Bechlioulis, A. & Milionis, H. Liberopoulos EJJoCD, Disease. Sinus bradycardia associated with remdesivir treatment in COVID-19: a case report and literature review. J. Cardiovasc. Dev. Dis. 8, 18 (2021).","journal-title":"J. Cardiovasc. Dev. Dis."},{"key":"46296_CR9","doi-asserted-by":"publisher","first-page":"11956","DOI":"10.1021\/ja504096m","volume":"136","author":"DA Ragland","year":"2014","unstructured":"Ragland, D. A. et al. Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease. J. Am. Chem. Soc. 136, 11956\u201311963 (2014).","journal-title":"J. Am. Chem. Soc."},{"key":"46296_CR10","doi-asserted-by":"publisher","first-page":"10792","DOI":"10.1074\/jbc.M610361200","volume":"282","author":"CL Johnson","year":"2007","unstructured":"Johnson, C. L. & Owen, D. M. Gale MJJoBC. Functional and therapeutic analysis of hepatitis C virus NS3\u00b7 4A protease control of antiviral immune defense. J. Biol. Chem. 282, 10792\u201310803 (2007).","journal-title":"J. Biol. Chem."},{"key":"46296_CR11","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","volume":"582","author":"Z Jin","year":"2020","unstructured":"Jin, Z. et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 582, 289\u2013293 (2020).","journal-title":"Nature"},{"key":"46296_CR12","first-page":"945","volume":"14","author":"T Bhardwaj","year":"2023","unstructured":"Bhardwaj, T. et al. Amyloidogenic proteins in the SARS-CoV and SARS-CoV-2. Proteomes 14, 945 (2023).","journal-title":"Proteomes"},{"key":"46296_CR13","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1126\/science.abl4784","volume":"374","author":"DR Owen","year":"2021","unstructured":"Owen, D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586\u20131593 (2021).","journal-title":"Science"},{"key":"46296_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26239-2","volume":"12","author":"B Boras","year":"2021","unstructured":"Boras, B. et al. Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nat. Commun. 12, 6055 (2021).","journal-title":"Nat. Commun."},{"key":"46296_CR15","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1002\/cpdd.1174","volume":"11","author":"T Zhu","year":"2022","unstructured":"Zhu, T. et al. Safety, tolerability, and pharmacokinetics of intravenous doses of PF\u201007304814, a phosphate prodrug protease inhibitor for the treatment of SARS\u2010CoV\u20102, in healthy adult participants. Clin. Pharmacol. Drug Dev. 11, 1382\u20131393 (2022).","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"46296_CR16","doi-asserted-by":"crossref","unstructured":"Wang, F. et al. Efficacy and safety of SIM0417 (SSD8432) plus ritonavir for COVID-19 treatment: a randomised, double-blind, placebo-controlled, phase 1b trial.  Lancet Reg. Health West. Pac. 38, 100835 (2023).","DOI":"10.1016\/j.lanwpc.2023.100835"},{"key":"46296_CR17","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1021\/acsptsci.0c00108","volume":"3","author":"W Zhu","year":"2020","unstructured":"Zhu, W. et al. Identification of SARS-CoV-2 3CL protease inhibitors by a quantitative high-throughput screening. ACS Pharmacol. Transl. Sci. 3, 1008\u20131016 (2020).","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"46296_CR18","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.ijid.2020.12.033","volume":"103","author":"J Liu","year":"2021","unstructured":"Liu, J. et al. A high-throughput drug screening strategy against coronaviruses. Int. J. Infect. Dis. 103, 300\u2013304 (2021).","journal-title":"Int. J. Infect. Dis."},{"key":"46296_CR19","doi-asserted-by":"publisher","first-page":"e667","DOI":"10.1016\/S2589-7500(20)30192-8","volume":"2","author":"Y Zhou","year":"2020","unstructured":"Zhou, Y., Wang, F., Tang, J., Nussinov, R. & Cheng, F. Artificial intelligence in COVID-19 drug repurposing. Lancet Digit. Health 2, e667\u2013e676 (2020).","journal-title":"Lancet Digit. Health"},{"key":"46296_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13578-021-00720-3","volume":"11","author":"G Yan","year":"2021","unstructured":"Yan, G. et al. Development of a simple and miniaturized sandwich-like fluorescence polarization assay for rapid screening of SARS-CoV-2 main protease inhibitors. Cell Biosci. 11, 1\u201314 (2021).","journal-title":"Cell Biosci."},{"key":"46296_CR21","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.1021\/acs.jcim.1c00404","volume":"61","author":"MA Llanos","year":"2021","unstructured":"Llanos, M. A. et al. Strengths and weaknesses of docking simulations in the SARS-CoV-2 era: the main protease (Mpro) case study. J. Chem. Inf. Model. 61, 3758\u20133770 (2021).","journal-title":"J. Chem. Inf. Model."},{"key":"46296_CR22","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1073\/pnas.0406847102","volume":"102","author":"OS Makin","year":"2005","unstructured":"Makin, O. S., Atkins, E., Sikorski, P., Johansson, J. & Serpell, L. C. Molecular basis for amyloid fibril formation and stability. Proc. Natl Acad. Sci. 102, 315\u2013320 (2005).","journal-title":"Proc. Natl Acad. Sci."},{"key":"46296_CR23","doi-asserted-by":"crossref","unstructured":"Lee, D. et al. Biomimetically engineered amyloid-shelled gold nanocomplexes for discovering \u03b1-synuclein oligomer-degrading drugs. ACS Appl. Mater. Interfaces. 15, 2538\u20132551 (2022).","DOI":"10.1021\/acsami.2c14650"},{"key":"46296_CR24","doi-asserted-by":"publisher","first-page":"3629","DOI":"10.1021\/bm200889k","volume":"12","author":"R Majithia","year":"2011","unstructured":"Majithia, R., Patterson, J., Bondos, S. E. & Meissner, K. E. On the design of composite protein\u2013quantum dot biomaterials via self-assembly. Biomacromolecules 12, 3629\u20133637 (2011).","journal-title":"Biomacromolecules"},{"key":"46296_CR25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-20314-w","volume":"12","author":"D Lee","year":"2021","unstructured":"Lee, D. et al. Plasmonic nanoparticle amyloid corona for screening A\u03b2 oligomeric aggregate-degrading drugs. Nat. Commun. 12, 1\u201311 (2021).","journal-title":"Nat. Commun."},{"key":"46296_CR26","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nnano.2012.62","volume":"7","author":"C Li","year":"2012","unstructured":"Li, C., Adamcik, J. & Mezzenga, R. Biodegradable nanocomposites of amyloid fibrils and graphene with shape-memory and enzyme-sensing properties. Nat. Nanotechnol. 7, 421\u2013427 (2012).","journal-title":"Nat. Nanotechnol."},{"key":"46296_CR27","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1039\/C7AN02013A","volume":"143","author":"D Lee","year":"2018","unstructured":"Lee, D., Lee, G. & Yoon, D. S. J. A. Anti-A\u03b2 drug candidates in clinical trials and plasmonic nanoparticle-based drug-screen for Alzheimer\u2019s disease. Analyst 143, 2204\u20132212 (2018).","journal-title":"Analyst"},{"key":"46296_CR28","doi-asserted-by":"publisher","first-page":"11242","DOI":"10.1002\/anie.201605151","volume":"55","author":"A Gladytz","year":"2016","unstructured":"Gladytz, A., Abel, B. & Risselada, H. J. Gold\u2010induced fibril growth: the mechanism of surface\u2010facilitated amyloid aggregation. Angew. Chem. Int. Ed. 55, 11242\u201311246 (2016).","journal-title":"Angew. Chem. Int. Ed."},{"key":"46296_CR29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2117142119","volume":"119","author":"Y Zhao","year":"2022","unstructured":"Zhao, Y. et al. Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2. Proc. Natl Acad. Sci. 119, e2117142119 (2022).","journal-title":"Proc. Natl Acad. Sci."},{"key":"46296_CR30","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","volume":"19","author":"P V\u2019kovski","year":"2021","unstructured":"V\u2019kovski, P., Kratzel, A., Steiner, S., Stalder, H. & Thiel, V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat. Rev. Microbiol. 19, 155\u2013170 (2021).","journal-title":"Nat. Rev. Microbiol."},{"key":"46296_CR31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","volume":"23","author":"CB Jackson","year":"2022","unstructured":"Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells.\u00a0Nat. Rev. Mol. Cell Biol.\u00a023, 3\u201320 (2022).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"46296_CR32","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1073\/pnas.2634884100","volume":"101","author":"M L\u00f3pez de la Paz","year":"2004","unstructured":"L\u00f3pez de la Paz, M. & Serrano, L. Sequence determinants of amyloid fibril formation. Proc. Natl Acad. Sci. 101, 87\u201392 (2004).","journal-title":"Proc. Natl Acad. Sci."},{"key":"46296_CR33","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1002\/pro.314","volume":"19","author":"S Tzotzos","year":"2010","unstructured":"Tzotzos, S. & Doig, A. J. J. P. S. Amyloidogenic sequences in native protein structures. Protein Sci. 19, 327\u2013348 (2010).","journal-title":"Protein Sci."},{"key":"46296_CR34","doi-asserted-by":"publisher","DOI":"10.1016\/j.nantod.2020.100937","volume":"35","author":"P Chen","year":"2020","unstructured":"Chen, P. et al. Amyloidosis inhibition, a new frontier of the protein corona. Nano Today 35, 100937 (2020).","journal-title":"Nano Today"},{"key":"46296_CR35","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nmat2442","volume":"8","author":"AE Nel","year":"2009","unstructured":"Nel, A. E. et al. Understanding biophysicochemical interactions at the nano\u2013bio interface. Nat. Mater. 8, 543\u2013557 (2009).","journal-title":"Nat. Mater."},{"key":"46296_CR36","doi-asserted-by":"publisher","first-page":"100272","DOI":"10.1016\/j.apsadv.2022.100272","volume":"11","author":"VP Brahmkhatri","year":"2022","unstructured":"Brahmkhatri, V. P. et al. Multilayer protein corona on gold nanorod surface: first evidence of soft corona protein-protein interactions using solution NMR spectroscopy. Appl. Surf. Sci. Adv. 11, 100272 (2022).","journal-title":"Appl. Surf. Sci. Adv."},{"key":"46296_CR37","doi-asserted-by":"publisher","first-page":"888","DOI":"10.3390\/nano11040888","volume":"11","author":"R Garc\u00eda-\u00c1lvarez","year":"2021","unstructured":"Garc\u00eda-\u00c1lvarez, R. & Vallet-Reg\u00ed, M. Hard and soft protein corona of nanomaterials: analysis and relevance. Nanomaterials 11, 888 (2021).","journal-title":"Nanomaterials"},{"key":"46296_CR38","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.3390\/s18061759","volume":"18","author":"W-T Wu","year":"2018","unstructured":"Wu, W.-T., Chen, C.-H., Chiang, C.-Y. & Chau, L.-K. Effect of surface coverage of gold nanoparticles on the refractive index sensitivity in fiber-optic nanoplasmonic sensing. Sensors 18, 1759 (2018).","journal-title":"Sensors"},{"key":"46296_CR39","doi-asserted-by":"publisher","first-page":"14096","DOI":"10.1021\/acsami.6b02548","volume":"8","author":"A Gupta","year":"2016","unstructured":"Gupta, A. et al. Ultrastable and biofunctionalizable gold nanoparticles. ACS Appl. Mater. Interfaces 8, 14096\u201314101 (2016).","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"46296_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11051-012-0758-z","volume":"14","author":"S Du","year":"2012","unstructured":"Du, S. et al. Aggregation and adhesion of gold nanoparticles in phosphate-buffered saline. J. Nanopart. Res. 14, 1\u201314 (2012).","journal-title":"J. Nanopart. Res."},{"key":"46296_CR41","doi-asserted-by":"publisher","first-page":"12544","DOI":"10.1021\/acscatal.0c03420","volume":"10","author":"CA Ramos-Guzm\u00e1n","year":"2020","unstructured":"Ramos-Guzm\u00e1n, C. A., Ruiz-Pern\u00eda, J. J., & Tu\u00f1\u00f3n, I. Unraveling the SARS-CoV-2 main protease mechanism using multiscale methods. ACS Catal. 10, 12544\u201312554 (2020).","journal-title":"ACS Catal."},{"key":"46296_CR42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-021-23313-7","volume":"12","author":"K Amporndanai","year":"2021","unstructured":"Amporndanai, K. et al. Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives. Nat. Commun. 12, 1\u20137 (2021).","journal-title":"Nat. Commun."},{"key":"46296_CR43","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd0345","volume":"6","author":"CA Men\u00e9ndez","year":"2020","unstructured":"Men\u00e9ndez, C. A., Byl\u00e9hn, F., Perez-Lemus, G. R., Alvarado, W. & de Pablo, J. J. Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease. Sci. Adv. 6, eabd0345 (2020).","journal-title":"Sci. Adv."},{"key":"46296_CR44","doi-asserted-by":"publisher","first-page":"e02220","DOI":"10.1128\/mBio.02220-21","volume":"12","author":"L Fu","year":"2021","unstructured":"Fu, L. et al. Mechanism of microbial metabolite leupeptin in the treatment of COVID-19 by traditional Chinese medicine herbs. Mbio 12, e02220\u2013e02221 (2021).","journal-title":"Mbio"},{"key":"46296_CR45","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1016\/j.str.2020.10.007","volume":"28","author":"DW Kneller","year":"2020","unstructured":"Kneller, D. W. et al. Malleability of the SARS-CoV-2 3CL Mpro active-site cavity facilitates binding of clinical antivirals. Structure 28, 1313\u20131320 (2020).","journal-title":"Structure"},{"key":"46296_CR46","doi-asserted-by":"publisher","first-page":"4110","DOI":"10.1080\/07391102.2020.1858164","volume":"40","author":"R Ghosh","year":"2022","unstructured":"Ghosh, R., Chakraborty, A., Biswas, A. & Chowdhuri, S. Depicting the inhibitory potential of polyphenols from Isatis indigotica root against the main protease of SARS CoV-2 using computational approaches. J. Biomol. Struct. Dyn. 40, 4110\u20134121 (2022).","journal-title":"J. Biomol. Struct. Dyn."},{"key":"46296_CR47","doi-asserted-by":"crossref","unstructured":"Fatriansyah, J. F., Rizqillah, R. K. & Yandi, M. Y. Molecular docking and molecular dynamics simulation of fisetin, galangin, hesperetin, hesperidin, myricetin, and naringenin against polymerase of dengue virus. J. Trop. Med. 2022, 12 (2022).","DOI":"10.1155\/2022\/7254990"},{"key":"46296_CR48","doi-asserted-by":"publisher","first-page":"2100028","DOI":"10.1002\/minf.202100028","volume":"40","author":"PA Nogara","year":"2021","unstructured":"Nogara, P. A. et al. In silico studies on the interaction between Mpro and PLpro From SARS\u2010CoV\u20102 and Ebselen, its metabolites and derivatives. Mol. Inform. 40, 2100028 (2021).","journal-title":"Mol. Inform."},{"key":"46296_CR49","doi-asserted-by":"publisher","first-page":"100038","DOI":"10.1016\/j.crphar.2021.100038","volume":"2","author":"D Verma","year":"2021","unstructured":"Verma, D. et al. Potential inhibitors of SARS-CoV-2 (COVID 19) proteases PLpro and Mpro\/3CLpro: molecular docking and simulation studies of three pertinent medicinal plant natural components. Curr. Res. Pharmacol. Drug Discov. 2, 100038 (2021).","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"46296_CR50","unstructured":"Elfiky, A. A. SARS-CoV-2 papain-like protease as a target for anti-HCV and anti-HIV proteases: in silico perspective. Int. J. Mol. Sci. 13, 242\u2013250 (2022)."},{"key":"46296_CR51","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.3390\/antiox11081618","volume":"11","author":"S-S Choi","year":"2022","unstructured":"Choi, S.-S., Lee, S.-H. & Lee, K.-A. A comparative study of hesperetin, hesperidin and hesperidin glucoside: antioxidant, anti-inflammatory, and antibacterial activities in vitro. Antioxidants 11, 1618 (2022).","journal-title":"Antioxidants"},{"key":"46296_CR52","doi-asserted-by":"crossref","unstructured":"Copeland, R. A. Evaluation of Enzyme Inhibitors in Drug Discovery: a Guide for Medicinal Chemists and Pharmacologists. John Wiley & Sons (2013).","DOI":"10.1002\/9781118540398"},{"key":"46296_CR53","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","volume":"19","author":"WT Harvey","year":"2021","unstructured":"Harvey, W. T. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 19, 409\u2013424 (2021).","journal-title":"Nat. Rev. Microbiol."},{"key":"46296_CR54","first-page":"3347","volume":"39","author":"S Das","year":"2021","unstructured":"Das, S., Sarmah, S., Lyndem, S., & Roy, A. S. An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study. J. Biomol. Struct. Dyn. 39, 3347\u20133357 (2021).","journal-title":"J. Biomol. Struct. Dyn."},{"key":"46296_CR55","doi-asserted-by":"publisher","first-page":"108","DOI":"10.2144\/btn-2020-0038","volume":"69","author":"B Cheng","year":"2020","unstructured":"Cheng, B. & Li, T. J. B. Discovery of alliin as a putative inhibitor of the main protease of SARS-CoV-2 by molecular docking. BioTechniques 69, 108\u2013112 (2020).","journal-title":"BioTechniques"},{"key":"46296_CR56","doi-asserted-by":"publisher","first-page":"4334","DOI":"10.1080\/07391102.2020.1776157","volume":"39","author":"S Gupta","year":"2021","unstructured":"Gupta, S. et al. Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies. J. Biomol. Struct. Dyn. 39, 4334\u20134345 (2021).","journal-title":"J. Biomol. Struct. Dyn."},{"key":"46296_CR57","doi-asserted-by":"crossref","unstructured":"Glaab E., Manoharan G. B. & Abankwa D. J. Pharmacophore model for SARS-CoV-2 3CLpro small-molecule inhibitors and in vitro experimental validation of computationally screened inhibitors. J. Chem. Inf. Model. 61, 4082\u20134096 (2021).","DOI":"10.1021\/acs.jcim.1c00258"},{"key":"46296_CR58","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bsheal.2020.11.007","volume":"3","author":"TML Souza","year":"2021","unstructured":"Souza, T. M. L., & Morel, C. M. The COVID-19 pandemic and the relevance of biosafety facilities for metagenomics surveillance, structured disease prevention and control. Biosaf. Health 3, 1\u20133 (2021).","journal-title":"Biosaf. Health"},{"key":"46296_CR59","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.4155\/fmc-2020-0158","volume":"12","author":"S Fan","year":"2020","unstructured":"Fan, S. et al. Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2. Fut. Med. Chem. 12, 1565\u20131578 (2020).","journal-title":"Fut. Med. Chem."},{"key":"46296_CR60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12985-020-01457-0","volume":"17","author":"M Mahdi","year":"2020","unstructured":"Mahdi, M. et al. Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2\u2032 s main protease. Virol. J. 17, 1\u20138 (2020).","journal-title":"Virol. J."},{"key":"46296_CR61","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.3390\/molecules26071924","volume":"26","author":"T Nguyen","year":"2021","unstructured":"Nguyen, T. et al. The inhibitory effects of plant derivate polyphenols on the main protease of SARS coronavirus 2 and their structure\u2013activity relationship. Molecules 26, 1924 (2021).","journal-title":"Molecules"},{"key":"46296_CR62","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nrd1382","volume":"3","author":"M Dickson","year":"2004","unstructured":"Dickson, M. & Gagnon, J. P. Key factors in the rising cost of new drug discovery and development. Nat. Rev. Drug Discov. 3, 417\u2013429 (2004).","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46296-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46296-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46296-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:04:50Z","timestamp":1710115490000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46296-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,7]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["46296"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-46296-7","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,7]]},"assertion":[{"value":"13 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2108"}}