Leveraging SARS-CoV-2 Main Protease (Mpro) for COVID-19 Mitigation with Selenium-Based Inhibitors
Viviana De Luca, Andrea Angeli, Alessio Nocentini, Paola Gratteri, Silvia Pratesi, Damiano Tanini, Vincenzo Carginale, Antonella Capperucci, Claudiu T Supuran, Clemente Capasso
International Journal of Molecular Sciences, doi:10.3390/ijms25020971
The implementation of innovative approaches is crucial in an ongoing endeavor to mitigate the impact of COVID-19 pandemic. The present study examines the strategic application of the SARS-CoV-2 Main Protease (M pro ) as a prospective instrument in the repertoire to combat the virus. The cloning, expression, and purification of M pro , which plays a critical role in the viral life cycle, through heterologous expression in Escherichia coli in a completely soluble form produced an active enzyme. The hydrolysis of a specific substrate peptide comprising a six-amino-acid sequence (TSAVLQ) linked to a p-nitroaniline (pNA) fragment together with the use of a fluorogenic substrate allowed us to determine effective inhibitors incorporating selenium moieties, such as benzoselenoates and carbamoselenoates. The new inhibitors revealed their potential to proficiently inhibit M pro with IC 50 -s in the low micromolar range. Our study contributes to the development of a new class of protease inhibitors targeting M pro , ultimately strengthening the antiviral arsenal against COVID-19 and possibly, related coronaviruses.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ijms25020971/s1.
Conflicts of Interest: The authors declare no conflicts of interest.
References
Ali, Benedetti, Handzlik, Zwergel, Battistelli, The innovative potential of seleniumcontaining agents for fighting cancer and viral infections, Drug Discov. Today,
doi:10.1016/j.drudis.2020.10.014Amporndanai, Meng, Shang, Jin, Rogers et al., Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives, Nat. Commun,
doi:10.1038/s41467-021-23313-7Angeli, Carta, Donnini, Capperucci, Ferraroni et al., Selenolesterase enzyme activity of carbonic anhydrases, Chem. Commun,
doi:10.1039/D0CC00995DAngeli, Ferraroni, Capperucci, Tanini, Costantino et al., Selenocarbamates As a Prodrug-Based Approach to Carbonic Anhydrase Inhibition, ChemMedChem,
doi:10.1002/cmdc.202200085Angeli, Tanini, Nocentini, Capperucci, Ferraroni et al., A new class of carbonic anhydrase inhibitors, Chem. Commun,
doi:10.1039/C8CC08562EBhardwaj, Singh, Das, Purohit, Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs, Comput. Biol. Med,
doi:10.1016/j.compbiomed.2020.104117Buxeraud, Faure, Fougere, Nirmatrelvir/ritonavir (Paxlovid(R)), a treatment for COVID-19, Actual. Pharm
Cao, Goreshnik, Coventry, Case, Miller et al., De novo design of picomolar SARS-CoV-2 miniprotein inhibitors, Science,
doi:10.1126/science.abd9909Capasso, Nocentini, Supuran, Protease inhibitors targeting the main protease and papain-like protease of coronaviruses, Expert Opin. Ther. Pat,
doi:10.1080/13543776.2021.1857726Capperucci, Petrucci, Faggi, Tanini, Click Reaction of Selenols with Isocyanates: Rapid Access to Selenocarbamates as Peroxide-Switchable Reservoir of Thiol-peroxidase-Like Catalysts, Adv. Synth. Catal,
doi:10.1002/adsc.202100611Carabelli, Peacock, Thorne, Harvey, Hughes et al., SARS-CoV-2 variant biology: Immune escape, transmission and fitness, Nat. Rev. Microbiol,
doi:10.1038/s41579-022-00841-7Chavda, Vuppu, Mishra, Kamaraj, Patel et al., Recent review of COVID-19 management: Diagnosis, treatment and vaccination, Pharmacol. Rep,
doi:10.1007/s43440-022-00425-5Chen, Shao, Peng, Liang, Xu et al., Review of preclinical data of PF-07304814 and its active metabolite derivatives against SARS-CoV-2 infection, Front. Pharmacol,
doi:10.3389/fphar.2022.1035969Citarella, Scala, Piperno, Micale, SARS-CoV-2 M pro : A Potential Target for Peptidomimetics and Small-Molecule Inhibitors, Biomolecules,
doi:10.3390/biom11040607Da Silva, Do Nascimento, Mendes, Guarines, Da Silva et al., Two Years into the COVID-19 Pandemic: Lessons Learned, ACS Infect. Dis,
doi:10.1021/acsinfecdis.2c00204Deniz, Uysal, Capasso, Supuran, Ozensoy Guler, Is carbonic anhydrase inhibition useful as a complementary therapy of COVID-19 infection?, J. Enzym. Inhib. Med. Chem,
doi:10.1080/14756366.2021.1924165Elnaggar, Elgazar, Gamal, Hamed, Elsayed et al., Identification of sulphonamide-tethered N-((triazol-4-yl)methyl)isatin derivatives as inhibitors of SARS-CoV-2 main protease, J. Enzym. Inhib. Med. Chem,
doi:10.1080/14756366.2023.2234665Eltayb, Abdalla, Rabie, Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir "S-217622": A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species, ACS Omega,
doi:10.1021/acsomega.2c03881Flynn, Samant, Schneider-Nachum, Barkan, Yilmaz et al., Comprehensive fitness landscape of SARS-CoV-2 M pro reveals insights into viral resistance mechanisms, eLife,
doi:10.7554/eLife.77433Ghosh, Mishevich, Mesecar, Mitsuya, Recent Drug Development and Medicinal Chemistry Approaches for the Treatment of SARS-CoV-2 Infection and COVID-19, ChemMedChem,
doi:10.1002/cmdc.202200440Hashemian, Sheida, Taghizadieh, Memar, Hamblin et al., Nirmatrelvir/Ritonavir): A new approach to COVID-19 therapy?, Biomed. Pharmacother,
doi:10.1016/j.biopha.2023.114367Hoffman, Kania, Brothers, Davies, Ferre et al., Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19, J. Med. Chem,
doi:10.1021/acs.jmedchem.0c01063Hou, Dong, Zhang, Wang, Su et al., Selenium as an emerging versatile player in heterocycles and natural products modification, Drug Discov. Today,
doi:10.1016/j.drudis.2022.03.020Hu, Xiong, Zhu, Zhang, Zhang et al., The SARS-CoV-2 main protease (M pro ): Structure, function, and emerging therapies for COVID-19, MedComm,
doi:10.1002/mco2.151Iacobucci, COVID-19: Evusheld protects the most vulnerable patients, analysis shows, BMJ-Br. Med. J,
doi:10.1136/bmj.o2690Ishihara, Koketsu, Fukuta, Nada, Reaction of lithium aluminum hydride with elemental selenium: Its application as a selenating reagent into organic molecules, J. Am. Chem. Soc,
doi:10.1021/ja005800oJiang, Zou, Zeng, Zeng, Zhou et al., Crystal structures of main protease (M pro ) mutants of SARS-CoV-2 variants bound to PF-07304814, Mol. Biomed,
doi:10.1186/s43556-023-00134-2Kabinger, Stiller, Schmitzova, Dienemann, Kokic et al., Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis, Nat. Struct. Mol. Biol,
doi:10.1038/s41594-021-00651-0Kamal, Ramadan, Farraj, Bahig, Ezzat, The pill of recovery; Molnupiravir for treatment of COVID-19 patients; a systematic review, Saudi Pharm. J,
doi:10.1016/j.jsps.2022.03.002Karniadakis, Mazonakis, Tsioutis, Papadakis, Markaki et al., Oral Molnupiravir and Nirmatrelvir/Ritonavir for the Treatment of COVID-19: A Literature Review with a Focus on Real-World Evidence, Infect. Dis. Rep,
doi:10.3390/idr15060061Kelley, De Moor, Douglas, Renshaw, Traviglia, Monoclonal antibody therapies for COVID-19: Lessons learned and implications for the development of future products, Curr. Opin. Biotechnol,
doi:10.1016/j.copbio.2022.102798Kip, Mccreary, Collins, Minnier, Snyder et al., Evolving Real-World Effectiveness of Monoclonal Antibodies for Treatment of COVID-19 A Cohort Study, Ann. Intern. Med,
doi:10.7326/M22-1286Kovacs, Kurtan, Varga, Nagy, Panyi et al., remdesivir) formulations inhibit initial membranecoupled events of SARS-CoV-2 infection due to their sulfobutylether-beta-cyclodextrin content, Br. J. Pharmacol,
doi:10.1111/bph.16063Li, Lin, Zhou, Zhong, Zeng et al., Structural Basis of Main Proteases of Coronavirus Bound to Drug Candidate PF-07304814, J. Mol. Biol,
doi:10.1016/j.jmb.2022.167706Li, Niu, A commentary on "The socio-economic implications of the coronavirus pandemic (COVID-19): A review, Int. J. Surg,
doi:10.1016/j.ijsu.2021.106048Li, Wang, Tian, Pang, Yang et al., COVID-19 vaccine development: Milestones, lessons and prospects, Signal Transduct. Target. Ther,
doi:10.1038/s41392-022-00996-yLiu, Wu, Huang, Hsu, Chuang et al., Clinical efficacy of nirmatrelvir plus ritonavir in patients with COVID-19 and preexisting cardiovascular diseases, Expert Rev. Anti-Infect. Ther,
doi:10.1080/14787210.2023.2284367Ma, Hu, Townsend, Lagarias, Marty et al., Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors, ACS Pharmacol. Transl. Sci,
doi:10.1021/acsptsci.0c00130Narayanan, Narwal, Majowicz, Varricchio, Toner et al., Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay, Commun. Biol,
doi:10.1038/s42003-022-03090-9Ng, Correia, Seagal, Degoey, Schrimpf et al., Antiviral Drug Discovery for the Treatment of COVID-19 Infections, Viruses,
doi:10.3390/v14050961Niknam, Jafari, Golchin, Danesh Pouya, Nemati et al., Potential therapeutic options for COVID-19: An update on current evidence, Eur. J. Med. Res,
doi:10.1186/s40001-021-00626-3Nocentini, Capasso, Supuran, Perspectives on the design and discovery of alpha-ketoamide inhibitors for the treatment of novel coronavirus: Where do we stand and where do we go?, Expert Opin. Drug Discov,
doi:10.1080/17460441.2022.2052847Pilote, Simard, Drolet, Remdesivir, VEKLURY) for Treating COVID-19: Guinea Pig Ex Vivo and In Vivo Cardiac Electrophysiological Effects, J. Cardiovasc. Pharmacol,
doi:10.1097/FJC.0000000000001321Ravaghi, Naidoo, Mataria, Khalil, Hospitals early challenges and interventions combatting COVID-19 in the Eastern Mediterranean Region, PLoS ONE,
doi:10.1371/journal.pone.0268386Ravi, Eerike, Konda, Bisoi, Raj et al., Efficacy and Safety of Anti-SARS-CoV-2 Monoclonal Antibodies: An Updated Review. Monoclon. Antibodies Immunodiagn, Immunother,
doi:10.1089/mab.2022.0036Razali, Subbiah, Budiman, Technical Data of Heterologous Expression and Purification of SARS-CoV-2 Proteases Using Escherichia coli System, Data,
doi:10.3390/data6090099Sacco, Ma, Lagarias, Gao, Townsend et al., Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M pro and cathepsin L, Sci. Adv,
doi:10.1126/sciadv.abe0751Sardar, Abdul-Khaliq, Ingar, Amaidia, Mansour, COVID-19 lockdown: A protective measure or exacerbator of health inequalities? A comparison between the United Kingdom and India.' a commentary on "the socio-economic implications of the coronavirus and COVID-19 pandemic: A review, Int. J. Surg,
doi:10.1016/j.ijsu.2020.09.044Sharun, Tiwari, Dhama, Dhama, Dexamethasone to combat cytokine storm in COVID-19: Clinical trials and preliminary evidence, Int. J. Surg,
doi:10.1016/j.ijsu.2020.08.038Tanini, Carradori, Capperucci, Lupori, Zara et al., Chalcogenides-incorporating carbonic anhydrase inhibitors concomitantly reverted oxaliplatin-induced neuropathy and enhanced antiproliferative action, Eur. J. Med. Chem,
doi:10.1016/j.ejmech.2021.113793Tanini, Scarpelli, Ermini, Capperucci, Seleno-Michael Reaction of Stable Functionalised Alkyl Selenols: A Versatile Tool for the Synthesis of Acyclic and Cyclic Unsymmetrical Alkyl and Vinyl Selenides, Adv. Synth. Catal,
doi:10.1002/adsc.201900168Tanini, Tiberi, Gellini, Salvi, Capperucci, A Straightforward Access to Stable β-Functionalized Alkyl Selenols, Adv. Synth. Catal,
doi:10.1002/adsc.201800602Thakkar, Agarwal, Ranaweera, Ishiguro, Conda-Sheridan et al., De novo design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain, RSC Med. Chem,
doi:10.1039/D3MD00222EWang, Yang, Yang, Hou, Tsai et al., Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug, Am. J. Cancer Res
Wynter-Adams, Thomas-Brown, COVID-19 vaccine hesitancy in a developing country: Prevalence, explanatory factors and implications for the future, Public Health,
doi:10.1016/j.puhe.2023.01.031Yadav, Chaudhary, Jain, Chaudhary, Khanra et al., Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19, Cells,
doi:10.3390/cells10040821Yang, Ju, Wang, Jia, Wang et al., Proxalutamide for the treatment of COVID-19 rebound following Paxlovid treatment: Report of four cases and review of the literature, J. Clin. Lab. Anal,
doi:10.1002/jcla.24880Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors, Science,
doi:10.1126/science.abb3405Zhao, Fang, Zhang, Zhang, Zhao et al., Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332, Protein Cell,
doi:10.1007/s13238-021-00883-2DOI record:
{
"DOI": "10.3390/ijms25020971",
"ISSN": [
"1422-0067"
],
"URL": "http://dx.doi.org/10.3390/ijms25020971",
"abstract": "<jats:p>The implementation of innovative approaches is crucial in an ongoing endeavor to mitigate the impact of COVID-19 pandemic. The present study examines the strategic application of the SARS-CoV-2 Main Protease (Mpro) as a prospective instrument in the repertoire to combat the virus. The cloning, expression, and purification of Mpro, which plays a critical role in the viral life cycle, through heterologous expression in Escherichia coli in a completely soluble form produced an active enzyme. The hydrolysis of a specific substrate peptide comprising a six-amino-acid sequence (TSAVLQ) linked to a p-nitroaniline (pNA) fragment together with the use of a fluorogenic substrate allowed us to determine effective inhibitors incorporating selenium moieties, such as benzoselenoates and carbamoselenoates. The new inhibitors revealed their potential to proficiently inhibit Mpro with IC50-s in the low micromolar range. Our study contributes to the development of a new class of protease inhibitors targeting Mpro, ultimately strengthening the antiviral arsenal against COVID-19 and possibly, related coronaviruses.</jats:p>",
"alternative-id": [
"ijms25020971"
],
"author": [
{
"affiliation": [
{
"name": "Department of Biology, Agriculture and Food Sciences, National Research Council (CNR), Institute of Biosciences and Bioresources, 80131 Naples, Italy"
}
],
"family": "De Luca",
"given": "Viviana",
"sequence": "first"
},
{
"ORCID": "http://orcid.org/0000-0002-1470-7192",
"affiliation": [
{
"name": "Neurofarba Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"
}
],
"authenticated-orcid": false,
"family": "Angeli",
"given": "Andrea",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0003-3342-702X",
"affiliation": [
{
"name": "Neurofarba Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"
}
],
"authenticated-orcid": false,
"family": "Nocentini",
"given": "Alessio",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0002-9137-2509",
"affiliation": [
{
"name": "Neurofarba Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"
}
],
"authenticated-orcid": false,
"family": "Gratteri",
"given": "Paola",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3-13, Sesto Fiorentino, 50019 Florence, Italy"
}
],
"family": "Pratesi",
"given": "Silvia",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0001-8930-3566",
"affiliation": [
{
"name": "Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3-13, Sesto Fiorentino, 50019 Florence, Italy"
}
],
"authenticated-orcid": false,
"family": "Tanini",
"given": "Damiano",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0002-1842-494X",
"affiliation": [
{
"name": "Department of Biology, Agriculture and Food Sciences, National Research Council (CNR), Institute of Biosciences and Bioresources, 80131 Naples, Italy"
}
],
"authenticated-orcid": false,
"family": "Carginale",
"given": "Vincenzo",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3-13, Sesto Fiorentino, 50019 Florence, Italy"
}
],
"family": "Capperucci",
"given": "Antonella",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0003-4262-0323",
"affiliation": [
{
"name": "Neurofarba Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"
}
],
"authenticated-orcid": false,
"family": "Supuran",
"given": "Claudiu T.",
"sequence": "additional"
},
{
"ORCID": "http://orcid.org/0000-0003-3314-2411",
"affiliation": [
{
"name": "Department of Biology, Agriculture and Food Sciences, National Research Council (CNR), Institute of Biosciences and Bioresources, 80131 Naples, Italy"
}
],
"authenticated-orcid": false,
"family": "Capasso",
"given": "Clemente",
"sequence": "additional"
}
],
"container-title": "International Journal of Molecular Sciences",
"container-title-short": "IJMS",
"content-domain": {
"crossmark-restriction": false,
"domain": []
},
"created": {
"date-parts": [
[
2024,
1,
12
]
],
"date-time": "2024-01-12T12:47:16Z",
"timestamp": 1705063636000
},
"deposited": {
"date-parts": [
[
2024,
1,
12
]
],
"date-time": "2024-01-12T13:12:11Z",
"timestamp": 1705065131000
},
"funder": [
{
"name": "Italian National Research Council"
}
],
"indexed": {
"date-parts": [
[
2024,
1,
13
]
],
"date-time": "2024-01-13T00:37:52Z",
"timestamp": 1705106272579
},
"is-referenced-by-count": 0,
"issue": "2",
"issued": {
"date-parts": [
[
2024,
1,
12
]
]
},
"journal-issue": {
"issue": "2",
"published-online": {
"date-parts": [
[
2024,
1
]
]
}
},
"language": "en",
"license": [
{
"URL": "https://creativecommons.org/licenses/by/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2024,
1,
12
]
],
"date-time": "2024-01-12T00:00:00Z",
"timestamp": 1705017600000
}
}
],
"link": [
{
"URL": "https://www.mdpi.com/1422-0067/25/2/971/pdf",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "1968",
"original-title": [],
"page": "971",
"prefix": "10.3390",
"published": {
"date-parts": [
[
2024,
1,
12
]
]
},
"published-online": {
"date-parts": [
[
2024,
1,
12
]
]
},
"publisher": "MDPI AG",
"reference": [
{
"DOI": "10.1038/s41579-023-00878-2",
"article-title": "The evolution of SARS-CoV-2",
"author": "Markov",
"doi-asserted-by": "crossref",
"first-page": "361",
"journal-title": "Nat. Rev. Microbiol.",
"key": "ref_1",
"volume": "21",
"year": "2023"
},
{
"DOI": "10.1016/j.ijsu.2021.106048",
"article-title": "A commentary on “The socio-economic implications of the coronavirus pandemic (COVID-19): A review”",
"author": "Li",
"doi-asserted-by": "crossref",
"first-page": "106048",
"journal-title": "Int. J. Surg.",
"key": "ref_2",
"volume": "95",
"year": "2021"
},
{
"DOI": "10.1016/j.ijsu.2020.09.044",
"article-title": "‘COVID-19 lockdown: A protective measure or exacerbator of health inequalities? A comparison between the United Kingdom and India.’ a commentary on “the socio-economic implications of the coronavirus and COVID-19 pandemic: A review”",
"author": "Sardar",
"doi-asserted-by": "crossref",
"first-page": "189",
"journal-title": "Int. J. Surg.",
"key": "ref_3",
"volume": "83",
"year": "2020"
},
{
"DOI": "10.1016/j.frl.2021.102245",
"article-title": "Stock market reactions to COVID-19 lockdown: A global analysis",
"author": "Scherf",
"doi-asserted-by": "crossref",
"first-page": "102245",
"journal-title": "Financ. Res. Lett.",
"key": "ref_4",
"volume": "45",
"year": "2022"
},
{
"DOI": "10.1016/j.puhip.2020.100061",
"article-title": "Pfizer: The miracle vaccine for COVID-19?",
"author": "Badiani",
"doi-asserted-by": "crossref",
"first-page": "100061",
"journal-title": "Public Health Pract.",
"key": "ref_5",
"volume": "1",
"year": "2020"
},
{
"article-title": "SARS-CoV-2 variant biology: Immune escape, transmission and fitness",
"author": "Carabelli",
"first-page": "162",
"journal-title": "Nat. Rev. Microbiol.",
"key": "ref_6",
"volume": "21",
"year": "2023"
},
{
"DOI": "10.1038/s41392-022-00996-y",
"article-title": "COVID-19 vaccine development: Milestones, lessons and prospects",
"author": "Li",
"doi-asserted-by": "crossref",
"first-page": "146",
"journal-title": "Signal Transduct. Target. Ther.",
"key": "ref_7",
"volume": "7",
"year": "2022"
},
{
"DOI": "10.1002/cmdc.202200440",
"article-title": "Recent Drug Development and Medicinal Chemistry Approaches for the Treatment of SARS-CoV-2 Infection and COVID-19",
"author": "Ghosh",
"doi-asserted-by": "crossref",
"first-page": "e202200440",
"journal-title": "ChemMedChem",
"key": "ref_8",
"volume": "17",
"year": "2022"
},
{
"DOI": "10.1097/MCP.0000000000000953",
"article-title": "Drug treatment of COVID-19 infection",
"author": "Lui",
"doi-asserted-by": "crossref",
"first-page": "174",
"journal-title": "Curr. Opin. Pulm. Med.",
"key": "ref_9",
"volume": "29",
"year": "2023"
},
{
"DOI": "10.1371/journal.pone.0268386",
"doi-asserted-by": "crossref",
"key": "ref_10",
"unstructured": "Ravaghi, H., Naidoo, V., Mataria, A., and Khalil, M. (2022). Hospitals early challenges and interventions combatting COVID-19 in the Eastern Mediterranean Region. PLoS ONE, 17."
},
{
"DOI": "10.1016/j.ijsu.2020.08.038",
"article-title": "Dexamethasone to combat cytokine storm in COVID-19: Clinical trials and preliminary evidence",
"author": "Sharun",
"doi-asserted-by": "crossref",
"first-page": "179",
"journal-title": "Int. J. Surg.",
"key": "ref_11",
"volume": "82",
"year": "2020"
},
{
"article-title": "Two Years into the COVID-19 Pandemic: Lessons Learned",
"author": "Mendes",
"first-page": "1758",
"journal-title": "ACS Infect. Dis.",
"key": "ref_12",
"volume": "8",
"year": "2020"
},
{
"DOI": "10.3390/futurepharmacol2040036",
"article-title": "Selenium-Based Drug Development for Antioxidant and Anticancer Activity",
"author": "Debnath",
"doi-asserted-by": "crossref",
"first-page": "595",
"journal-title": "Future Pharmacol.",
"key": "ref_13",
"volume": "2",
"year": "2022"
},
{
"DOI": "10.1016/j.drudis.2020.10.014",
"article-title": "The innovative potential of seleniumcontaining agents for fighting cancer and viral infections",
"author": "Ali",
"doi-asserted-by": "crossref",
"first-page": "256",
"journal-title": "Drug Discov. Today",
"key": "ref_14",
"volume": "26",
"year": "2021"
},
{
"DOI": "10.1016/j.drudis.2022.03.020",
"article-title": "Selenium as an emerging versatile player in heterocycles and natural products modification",
"author": "Hou",
"doi-asserted-by": "crossref",
"first-page": "2268",
"journal-title": "Drug Discov. Today",
"key": "ref_15",
"volume": "27",
"year": "2022"
},
{
"DOI": "10.1002/cmdc.202200085",
"article-title": "Selenocarbamates As a Prodrug-Based Approach to Carbonic Anhydrase Inhibition",
"author": "Angeli",
"doi-asserted-by": "crossref",
"first-page": "e202200085",
"journal-title": "ChemMedChem",
"key": "ref_16",
"volume": "17",
"year": "2022"
},
{
"DOI": "10.1016/j.ejmech.2021.113793",
"article-title": "Chalcogenides-incorporating carbonic anhydrase inhibitors concomitantly reverted oxaliplatin-induced neuropathy and enhanced antiproliferative action",
"author": "Tanini",
"doi-asserted-by": "crossref",
"first-page": "113793",
"journal-title": "Eur. J. Med. Chem.",
"key": "ref_17",
"volume": "225",
"year": "2021"
},
{
"DOI": "10.1038/s41586-020-2223-y",
"article-title": "Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors",
"author": "Jin",
"doi-asserted-by": "crossref",
"first-page": "289",
"journal-title": "Nature",
"key": "ref_18",
"volume": "582",
"year": "2020"
},
{
"DOI": "10.1021/acsptsci.0c00130",
"article-title": "Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors",
"author": "Ma",
"doi-asserted-by": "crossref",
"first-page": "1265",
"journal-title": "ACS Pharmacol. Transl. Sci.",
"key": "ref_19",
"volume": "3",
"year": "2020"
},
{
"DOI": "10.1038/s41467-021-23313-7",
"article-title": "Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives",
"author": "Amporndanai",
"doi-asserted-by": "crossref",
"first-page": "3061",
"journal-title": "Nat. Commun.",
"key": "ref_20",
"volume": "12",
"year": "2021"
},
{
"DOI": "10.1111/bph.16063",
"article-title": "Veklury(R) (remdesivir) formulations inhibit initial membrane-coupled events of SARS-CoV-2 infection due to their sulfobutylether-beta-cyclodextrin content",
"author": "Kovacs",
"doi-asserted-by": "crossref",
"first-page": "2064",
"journal-title": "Br. J. Pharmacol.",
"key": "ref_21",
"volume": "180",
"year": "2023"
},
{
"DOI": "10.1097/FJC.0000000000001321",
"article-title": "Remdesivir (VEKLURY) for Treating COVID-19: Guinea Pig Ex Vivo and In Vivo Cardiac Electrophysiological Effects",
"author": "Pilote",
"doi-asserted-by": "crossref",
"first-page": "616",
"journal-title": "J. Cardiovasc. Pharmacol.",
"key": "ref_22",
"volume": "80",
"year": "2022"
},
{
"DOI": "10.1016/j.copbio.2022.102798",
"article-title": "Monoclonal antibody therapies for COVID-19: Lessons learned and implications for the development of future products",
"author": "Kelley",
"doi-asserted-by": "crossref",
"first-page": "102798",
"journal-title": "Curr. Opin. Biotechnol.",
"key": "ref_23",
"volume": "78",
"year": "2022"
},
{
"DOI": "10.1089/mab.2022.0036",
"article-title": "Efficacy and Safety of Anti-SARS-CoV-2 Monoclonal Antibodies: An Updated Review",
"author": "Ravi",
"doi-asserted-by": "crossref",
"first-page": "77",
"journal-title": "Monoclon. Antibodies Immunodiagn. Immunother.",
"key": "ref_24",
"volume": "42",
"year": "2023"
},
{
"article-title": "Nasally Administered Monoclonal Antibody for COVID-19",
"author": "Harris",
"first-page": "1142",
"journal-title": "JAMA-J. Am. Med. Assoc.",
"key": "ref_25",
"volume": "329",
"year": "2023"
},
{
"DOI": "10.7326/M22-1286",
"article-title": "Evolving Real-World Effectiveness of Monoclonal Antibodies for Treatment of COVID-19 A Cohort Study",
"author": "Kip",
"doi-asserted-by": "crossref",
"first-page": "496",
"journal-title": "Ann. Intern. Med.",
"key": "ref_26",
"volume": "176",
"year": "2023"
},
{
"DOI": "10.1016/j.puhe.2023.01.031",
"article-title": "COVID-19 vaccine hesitancy in a developing country: Prevalence, explanatory factors and implications for the future",
"doi-asserted-by": "crossref",
"first-page": "146",
"journal-title": "Public Health",
"key": "ref_27",
"volume": "217",
"year": "2023"
},
{
"DOI": "10.1136/bmj.o2690",
"article-title": "COVID-19: Evusheld protects the most vulnerable patients, analysis shows",
"author": "Iacobucci",
"doi-asserted-by": "crossref",
"first-page": "o2690",
"journal-title": "BMJ-Br. Med. J.",
"key": "ref_28",
"volume": "379",
"year": "2022"
},
{
"DOI": "10.1186/s40001-021-00626-3",
"article-title": "Potential therapeutic options for COVID-19: An update on current evidence",
"author": "Niknam",
"doi-asserted-by": "crossref",
"first-page": "6",
"journal-title": "Eur. J. Med. Res.",
"key": "ref_29",
"volume": "27",
"year": "2022"
},
{
"DOI": "10.3390/v14050961",
"doi-asserted-by": "crossref",
"key": "ref_30",
"unstructured": "Ng, T.I., Correia, I., Seagal, J., DeGoey, D.A., Schrimpf, M.R., Hardee, D.J., Noey, E.L., and Kati, W.M. (2022). Antiviral Drug Discovery for the Treatment of COVID-19 Infections. Viruses, 14."
},
{
"DOI": "10.1038/s41594-021-00651-0",
"article-title": "Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis",
"author": "Kabinger",
"doi-asserted-by": "crossref",
"first-page": "740",
"journal-title": "Nat. Struct. Mol. Biol.",
"key": "ref_31",
"volume": "28",
"year": "2021"
},
{
"DOI": "10.1016/j.jsps.2022.03.002",
"article-title": "The pill of recovery; Molnupiravir for treatment of COVID-19 patients; a systematic review",
"author": "Kamal",
"doi-asserted-by": "crossref",
"first-page": "508",
"journal-title": "Saudi Pharm. J.",
"key": "ref_32",
"volume": "30",
"year": "2022"
},
{
"article-title": "Nirmatrelvir/ritonavir (Paxlovid(R)), a treatment for COVID-19",
"author": "Buxeraud",
"first-page": "10",
"journal-title": "Actual. Pharm.",
"key": "ref_33",
"volume": "61",
"year": "2022"
},
{
"DOI": "10.1002/jcla.24880",
"article-title": "Proxalutamide for the treatment of COVID-19 rebound following Paxlovid treatment: Report of four cases and review of the literature",
"author": "Yang",
"doi-asserted-by": "crossref",
"first-page": "e24880",
"journal-title": "J. Clin. Lab. Anal.",
"key": "ref_34",
"volume": "37",
"year": "2023"
},
{
"DOI": "10.1007/s43440-022-00425-5",
"article-title": "Recent review of COVID-19 management: Diagnosis, treatment and vaccination",
"author": "Chavda",
"doi-asserted-by": "crossref",
"first-page": "1120",
"journal-title": "Pharmacol. Rep.",
"key": "ref_35",
"volume": "74",
"year": "2022"
},
{
"DOI": "10.1016/j.biopha.2023.114367",
"doi-asserted-by": "crossref",
"key": "ref_36",
"unstructured": "Hashemian, S.M.R., Sheida, A., Taghizadieh, M., Memar, M.Y., Hamblin, M.R., Bannazadeh Baghi, H., Sadri Nahand, J., Asemi, Z., and Mirzaei, H. (2023). Paxlovid (Nirmatrelvir/Ritonavir): A new approach to COVID-19 therapy?. Biomed. Pharmacother., 162."
},
{
"DOI": "10.1021/acsomega.2c03881",
"article-title": "Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir “S-217622”: A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species",
"author": "Eltayb",
"doi-asserted-by": "crossref",
"first-page": "5234",
"journal-title": "ACS Omega",
"key": "ref_37",
"volume": "8",
"year": "2023"
},
{
"DOI": "10.3390/cells10040821",
"doi-asserted-by": "crossref",
"key": "ref_38",
"unstructured": "Yadav, R., Chaudhary, J.K., Jain, N., Chaudhary, P.K., Khanra, S., Dhamija, P., Sharma, A., Kumar, A., and Handu, S. (2021). Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19. Cells, 10."
},
{
"DOI": "10.1080/13543776.2020.1760838",
"article-title": "A deadly spillover: SARS-CoV-2 outbreak",
"author": "Mori",
"doi-asserted-by": "crossref",
"first-page": "481",
"journal-title": "Expert Opin. Ther. Pat.",
"key": "ref_39",
"volume": "30",
"year": "2020"
},
{
"DOI": "10.1080/13543776.2021.1857726",
"article-title": "Protease inhibitors targeting the main protease and papain-like protease of coronaviruses",
"author": "Capasso",
"doi-asserted-by": "crossref",
"first-page": "309",
"journal-title": "Expert Opin. Ther. Pat.",
"key": "ref_40",
"volume": "31",
"year": "2021"
},
{
"DOI": "10.1080/14756366.2021.1924165",
"article-title": "Is carbonic anhydrase inhibition useful as a complementary therapy of COVID-19 infection?",
"author": "Deniz",
"doi-asserted-by": "crossref",
"first-page": "1230",
"journal-title": "J. Enzym. Inhib. Med. Chem.",
"key": "ref_41",
"volume": "36",
"year": "2021"
},
{
"DOI": "10.3390/biom11040607",
"doi-asserted-by": "crossref",
"key": "ref_42",
"unstructured": "Citarella, A., Scala, A., Piperno, A., and Micale, N. (2021). SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors. Biomolecules, 11."
},
{
"DOI": "10.7554/eLife.77433",
"article-title": "Comprehensive fitness landscape of SARS-CoV-2 Mpro reveals insights into viral resistance mechanisms",
"author": "Flynn",
"doi-asserted-by": "crossref",
"first-page": "e77433",
"journal-title": "eLife",
"key": "ref_43",
"volume": "11",
"year": "2022"
},
{
"article-title": "The SARS-CoV-2 main protease (Mpro): Structure, function, and emerging therapies for COVID-19",
"author": "Hu",
"first-page": "e151",
"journal-title": "MedComm (2020)",
"key": "ref_44",
"volume": "3",
"year": "2022"
},
{
"DOI": "10.3389/fchem.2021.622898",
"article-title": "Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease",
"author": "Mengist",
"doi-asserted-by": "crossref",
"first-page": "622898",
"journal-title": "Front. Chem.",
"key": "ref_45",
"volume": "9",
"year": "2021"
},
{
"DOI": "10.1016/j.pep.2011.08.005",
"article-title": "An overview of enzymatic reagents for the removal of affinity tags",
"author": "Waugh",
"doi-asserted-by": "crossref",
"first-page": "283",
"journal-title": "Protein Expr. Purif.",
"key": "ref_46",
"volume": "80",
"year": "2011"
},
{
"DOI": "10.1126/science.abb3405",
"article-title": "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors",
"author": "Zhang",
"doi-asserted-by": "crossref",
"first-page": "409",
"journal-title": "Science",
"key": "ref_47",
"volume": "368",
"year": "2020"
},
{
"DOI": "10.3390/data6090099",
"doi-asserted-by": "crossref",
"key": "ref_48",
"unstructured": "Razali, R., Subbiah, V.K., and Budiman, C. (2021). Technical Data of Heterologous Expression and Purification of SARS-CoV-2 Proteases Using Escherichia coli System. Data, 6."
},
{
"DOI": "10.1126/sciadv.abe0751",
"article-title": "Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L",
"author": "Sacco",
"doi-asserted-by": "crossref",
"first-page": "eabe0751",
"journal-title": "Sci. Adv.",
"key": "ref_49",
"volume": "6",
"year": "2020"
},
{
"DOI": "10.1016/j.compbiomed.2020.104117",
"article-title": "Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs",
"author": "Bhardwaj",
"doi-asserted-by": "crossref",
"first-page": "104117",
"journal-title": "Comput. Biol. Med.",
"key": "ref_50",
"volume": "128",
"year": "2021"
},
{
"DOI": "10.1016/j.bmcl.2020.127377",
"article-title": "The SARS-CoV-2 main protease as drug target",
"author": "Ullrich",
"doi-asserted-by": "crossref",
"first-page": "127377",
"journal-title": "Bioorganic Med. Chem. Lett.",
"key": "ref_51",
"volume": "30",
"year": "2020"
},
{
"DOI": "10.1007/s13238-021-00883-2",
"article-title": "Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332",
"author": "Zhao",
"doi-asserted-by": "crossref",
"first-page": "689",
"journal-title": "Protein Cell",
"key": "ref_52",
"volume": "13",
"year": "2022"
},
{
"DOI": "10.3389/fphar.2022.1035969",
"article-title": "Review of preclinical data of PF-07304814 and its active metabolite derivatives against SARS-CoV-2 infection",
"author": "Chen",
"doi-asserted-by": "crossref",
"first-page": "1035969",
"journal-title": "Front. Pharmacol.",
"key": "ref_53",
"volume": "13",
"year": "2022"
},
{
"DOI": "10.1186/s43556-023-00134-2",
"article-title": "Crystal structures of main protease (Mpro) mutants of SARS-CoV-2 variants bound to PF-07304814",
"author": "Jiang",
"doi-asserted-by": "crossref",
"first-page": "23",
"journal-title": "Mol. Biomed.",
"key": "ref_54",
"volume": "4",
"year": "2023"
},
{
"DOI": "10.1016/j.jmb.2022.167706",
"article-title": "Structural Basis of Main Proteases of Coronavirus Bound to Drug Candidate PF-07304814",
"author": "Li",
"doi-asserted-by": "crossref",
"first-page": "167706",
"journal-title": "J. Mol. Biol.",
"key": "ref_55",
"volume": "434",
"year": "2022"
},
{
"DOI": "10.3390/idr15060061",
"article-title": "Oral Molnupiravir and Nirmatrelvir/Ritonavir for the Treatment of COVID-19: A Literature Review with a Focus on Real-World Evidence",
"author": "Karniadakis",
"doi-asserted-by": "crossref",
"first-page": "662",
"journal-title": "Infect. Dis. Rep.",
"key": "ref_56",
"volume": "15",
"year": "2023"
},
{
"DOI": "10.1080/14787210.2023.2284367",
"doi-asserted-by": "crossref",
"key": "ref_57",
"unstructured": "Liu, T.H., Wu, J.Y., Huang, P.Y., Hsu, W.H., Chuang, M.H., Tsai, Y.W., Lai, C.C., and Huang, C.Y. (2023). Clinical efficacy of nirmatrelvir plus ritonavir in patients with COVID-19 and preexisting cardiovascular diseases. Expert Rev. Anti-Infect. Ther., 1–8."
},
{
"DOI": "10.1002/adsc.202101147",
"article-title": "Synthesis and Applications of Organic Selenols",
"author": "Tanini",
"doi-asserted-by": "crossref",
"first-page": "5360",
"journal-title": "Adv. Synth. Catal.",
"key": "ref_58",
"volume": "363",
"year": "2021"
},
{
"DOI": "10.1002/adsc.201900168",
"article-title": "Seleno-Michael Reaction of Stable Functionalised Alkyl Selenols: A Versatile Tool for the Synthesis of Acyclic and Cyclic Unsymmetrical Alkyl and Vinyl Selenides",
"author": "Tanini",
"doi-asserted-by": "crossref",
"first-page": "2337",
"journal-title": "Adv. Synth. Catal.",
"key": "ref_59",
"volume": "361",
"year": "2019"
},
{
"DOI": "10.1002/adsc.201800602",
"article-title": "A Straightforward Access to Stable β-Functionalized Alkyl Selenols",
"author": "Tanini",
"doi-asserted-by": "crossref",
"first-page": "3367",
"journal-title": "Adv. Synth. Catal.",
"key": "ref_60",
"volume": "360",
"year": "2018"
},
{
"DOI": "10.1039/C8CC08562E",
"article-title": "Selenols: A new class of carbonic anhydrase inhibitors",
"author": "Angeli",
"doi-asserted-by": "crossref",
"first-page": "648",
"journal-title": "Chem. Commun.",
"key": "ref_61",
"volume": "55",
"year": "2019"
},
{
"DOI": "10.1039/D0CC00995D",
"article-title": "Selenolesterase enzyme activity of carbonic anhydrases",
"author": "Angeli",
"doi-asserted-by": "crossref",
"first-page": "4444",
"journal-title": "Chem. Commun.",
"key": "ref_62",
"volume": "56",
"year": "2020"
},
{
"DOI": "10.1002/adsc.202100611",
"article-title": "Click Reaction of Selenols with Isocyanates: Rapid Access to Selenocarbamates as Peroxide-Switchable Reservoir of Thiol-peroxidase-Like Catalysts",
"author": "Capperucci",
"doi-asserted-by": "crossref",
"first-page": "4256",
"journal-title": "Adv. Synth. Catal.",
"key": "ref_63",
"volume": "363",
"year": "2021"
},
{
"DOI": "10.1021/ja005800o",
"article-title": "Reaction of lithium aluminum hydride with elemental selenium: Its application as a selenating reagent into organic molecules",
"author": "Ishihara",
"doi-asserted-by": "crossref",
"first-page": "8408",
"journal-title": "J. Am. Chem. Soc.",
"key": "ref_64",
"volume": "123",
"year": "2001"
},
{
"DOI": "10.1126/science.abd9909",
"article-title": "De novo design of picomolar SARS-CoV-2 miniprotein inhibitors",
"author": "Cao",
"doi-asserted-by": "crossref",
"first-page": "426",
"journal-title": "Science",
"key": "ref_65",
"volume": "370",
"year": "2020"
},
{
"DOI": "10.1039/D3MD00222E",
"article-title": "De novo design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain",
"author": "Thakkar",
"doi-asserted-by": "crossref",
"first-page": "1722",
"journal-title": "RSC Med. Chem.",
"key": "ref_66",
"volume": "14",
"year": "2023"
},
{
"DOI": "10.1021/acs.jmedchem.0c01063",
"article-title": "Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19",
"author": "Hoffman",
"doi-asserted-by": "crossref",
"first-page": "12725",
"journal-title": "J. Med. Chem.",
"key": "ref_67",
"volume": "63",
"year": "2020"
},
{
"DOI": "10.1038/s42003-022-03090-9",
"article-title": "Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay",
"author": "Narayanan",
"doi-asserted-by": "crossref",
"first-page": "169",
"journal-title": "Commun. Biol.",
"key": "ref_68",
"volume": "5",
"year": "2022"
},
{
"article-title": "Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug",
"author": "Wang",
"first-page": "2535",
"journal-title": "Am. J. Cancer Res.",
"key": "ref_69",
"volume": "10",
"year": "2020"
},
{
"key": "ref_70",
"unstructured": "Schrödinger Suite Release 2022-4 (2022). (a) Maestro v.13.2; (b) Prime, v.5.5; (c) Epik, v.6.0; (d) Impact, v.9.5; (e) Macromodel v.13.6. (f) Glide, v.9.5, Schrödinger, LLC."
},
{
"DOI": "10.1080/17460441.2022.2052847",
"article-title": "Perspectives on the design and discovery of alpha-ketoamide inhibitors for the treatment of novel coronavirus: Where do we stand and where do we go?",
"author": "Nocentini",
"doi-asserted-by": "crossref",
"first-page": "547",
"journal-title": "Expert Opin. Drug Discov.",
"key": "ref_71",
"volume": "17",
"year": "2022"
},
{
"DOI": "10.1080/14756366.2023.2234665",
"article-title": "Identification of sulphonamide-tethered N-((triazol-4-yl)methyl)isatin derivatives as inhibitors of SARS-CoV-2 main protease",
"author": "ElNaggar",
"doi-asserted-by": "crossref",
"first-page": "2234665",
"journal-title": "J. Enzym. Inhib. Med. Chem.",
"key": "ref_72",
"volume": "38",
"year": "2023"
}
],
"reference-count": 72,
"references-count": 72,
"relation": {},
"resource": {
"primary": {
"URL": "https://www.mdpi.com/1422-0067/25/2/971"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [
"Inorganic Chemistry",
"Organic Chemistry",
"Physical and Theoretical Chemistry",
"Computer Science Applications",
"Spectroscopy",
"Molecular Biology",
"General Medicine",
"Catalysis"
],
"subtitle": [],
"title": "Leveraging SARS-CoV-2 Main Protease (Mpro) for COVID-19 Mitigation with Selenium-Based Inhibitors",
"type": "journal-article",
"volume": "25"
}
