{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:12:13Z","timestamp":1791569533560,"version":"4.3.4"},"reference-count":100,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,18]],"date-time":"2025-05-18T00:00:00Z","timestamp":1747526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The COVID-19 pandemic has had a significant impact and continues to alarm the entire world due to the rapid emergence of new variants, even after mass vaccinations. There is still an urgent need for new antivirals or strategies to combat the SARS-CoV-2 infections; however, we have success stories with nirmatrelvir. Drug repurposing and drug discovery may lead to a successful SARS-CoV-2 antiviral; however, rapid drug use may cause unexpected mutations and antiviral drug resistance. Conversely, novel variants of the SARS-CoV-2 can diminish the neutralizing efficacy of vaccines, thereby enhancing viral fitness and increasing the likelihood of drug resistance emergence. Additionally, the disposal of antivirals in wastewater also contributes to drug resistance. Overall, the present review summarizes the strategies and mechanisms involved in the development of drug resistance in SARS-CoV-2. Understanding the mechanism of antiviral resistance is crucial to mitigate the significant healthcare threat and to develop effective therapeutics against drug resistance.<\/jats:p>","DOI":"10.3390\/v17050722","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T06:54:28Z","timestamp":1747724068000},"page":"722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Evolution of Antiviral Drug Resistance in SARS-CoV-2"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1841-2305","authenticated-orcid":false,"given":"Roy","family":"Dinata","sequence":"first","affiliation":[{"name":"Animal Science Research Center, Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5620-633X","authenticated-orcid":false,"given":"Piyush","family":"Baindara","sequence":"additional","affiliation":[{"name":"Animal Science Research Center, Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-7138","authenticated-orcid":false,"given":"Santi M.","family":"Mandal","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"n436","DOI":"10.1136\/bmj.n436","article-title":"Severe COVID-19 pneumonia: Pathogenesis and clinical management","volume":"372","author":"Attaway","year":"2021","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1080\/17476348.2020.1804365","article-title":"Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: A systematic review and meta-analysis","volume":"14","author":"Hasan","year":"2020","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lopes-Pacheco, M., Silva, P.L., Cruz, F.F., Battaglini, D., Robba, C., Pelosi, P., Morales, M.M., Caruso Neves, C., and Rocco, P.R.M. (2021). Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.593223"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/j.jiph.2020.07.003","article-title":"Molecular pathogenesis of secondary bacterial infection associated to viral infections including SARS-CoV-2","volume":"13","author":"Manna","year":"2020","journal-title":"J. Infect. Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1186\/s12967-020-02439-0","article-title":"Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach","volume":"18","author":"Aftab","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_6","first-page":"3204","article-title":"SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: An in silico perspective","volume":"39","author":"Elfiky","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117592","DOI":"10.1016\/j.lfs.2020.117592","article-title":"Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study","volume":"253","author":"Elfiky","year":"2020","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jgg.2020.02.001","article-title":"Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines","volume":"47","author":"Liu","year":"2020","journal-title":"J. Genet. Genom."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104793","DOI":"10.1016\/j.antiviral.2020.104793","article-title":"Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites","volume":"178","author":"Shannon","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e00221-18","DOI":"10.1128\/mBio.00221-18","article-title":"Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease","volume":"9","author":"Agostini","year":"2018","journal-title":"mBio"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1021\/acsbiomedchemau.4c00045","article-title":"An Investigation of Nirmatrelvir (Paxlovid) Resistance in SARS-CoV-2 Mpro","volume":"4","author":"Yaghi","year":"2024","journal-title":"ACS Bio. Med. Chem. Au."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lauring, A.S., and Andino, R. (2010). Quasispecies theory and the behavior of RNA viruses. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001005"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.coviro.2019.04.002","article-title":"Nucleoside analogues for the treatment of coronavirus infections","volume":"35","author":"Pruijssers","year":"2019","journal-title":"Curr. Opin. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Szemiel, A.M., Merits, A., Orton, R.J., MacLean, O.A., Pinto, R.M., Wickenhagen, A., Lieber, G., Turnbull, M.L., Wang, S., and Furnon, W. (2021). In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009929"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11886","DOI":"10.1128\/JVI.01528-14","article-title":"Coronaviruses Resistant to a 3C-Like Protease Inhibitor are Attenuated for Replication and Pathogenesis, Revealing a Low Genetic Barrier but High Fitness Cost of Resistance","volume":"88","author":"Deng","year":"2014","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e01348-19","DOI":"10.1128\/JVI.01348-19","article-title":"Small-molecule antiviral \u03b2-d-N 4-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance","volume":"93","author":"Agostini","year":"2019","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eabb5883","DOI":"10.1126\/scitranslmed.abb5883","article-title":"An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice","volume":"12","author":"Sheahan","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1186\/s13063-021-05538-5","article-title":"Accelerated first-in-human clinical trial of EIDD-2801\/MK-4482 (molnupiravir), a ribonucleoside analog with potent antiviral activity against SARS-CoV-2","volume":"22","author":"Holman","year":"2021","journal-title":"Trials"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa2116044","article-title":"Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients","volume":"386","author":"Musungaie","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100721","DOI":"10.1016\/j.drup.2020.100721","article-title":"Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses","volume":"53","author":"Artese","year":"2020","journal-title":"Drug Resist. Updat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2024302118","DOI":"10.1073\/pnas.2024302118","article-title":"Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay","volume":"118","author":"Jang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41576-021-00408-x","article-title":"The biological and clinical significance of emerging SARS-CoV-2 variants","volume":"22","author":"Tao","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.cell.2020.06.043","article-title":"Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus","volume":"182","author":"Korber","year":"2020","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41586-021-03470-x","article-title":"Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England","volume":"593","author":"Volz","year":"2021","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/d41586-021-03619-8","article-title":"Beyond Omicron: What\u2019s next for COVID\u2019s viral evolution","volume":"600","author":"Callaway","year":"2021","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41586-021-03807-6","article-title":"SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape","volume":"597","author":"Starr","year":"2021","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1038\/s41564-021-00954-4","article-title":"SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution","volume":"6","author":"Marciano","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/s41467-022-28287-8","article-title":"SARS-CoV-2 genomes from Saudi Arabia implicate nucleocapsid mutations in host response and increased viral load","volume":"13","author":"Mourier","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e41980","DOI":"10.1016\/j.heliyon.2025.e41980","article-title":"SARS-CoV-2 drug resistance and therapeutic approaches","volume":"11","author":"Batool","year":"2025","journal-title":"Heliyon"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41586-021-03398-2","article-title":"Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7","volume":"593","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e202101049","DOI":"10.26508\/lsa.202101049","article-title":"Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection","volume":"4","author":"Kim","year":"2021","journal-title":"Life Sci. Alliance"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1080\/23744235.2023.2238077","article-title":"Combination of two rare mutations in the SARS-CoV-2 M gene in patients with severe and prolonged COVID-19","volume":"55","author":"Trifonova","year":"2023","journal-title":"Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shah, D., Freas, C., Weber, I.T., and Harrison, R.W. (2020). Evolution of drug resistance in HIV protease. BMC Bioinform., 21.","DOI":"10.1186\/s12859-020-03825-7"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2100425118","DOI":"10.1073\/pnas.2100425118","article-title":"Dual nature of human ACE2 glycosylation in binding to SARS-CoV-2 spike","volume":"118","author":"Mehdipour","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e61552","DOI":"10.7554\/eLife.61552","article-title":"Inhibition of SARS-CoV-2 viral entry upon blocking N-and O-glycan elaboration","volume":"9","author":"Yang","year":"2020","journal-title":"Elife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41392-021-00809-8","article-title":"The glycosylation in SARS-CoV-2 and its receptor ACE2","volume":"6","author":"Gong","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e01031-17","DOI":"10.1128\/JVI.01031-17","article-title":"Complexities of Viral Mutation Rates","volume":"92","author":"Peck","year":"2018","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kosuge, M., Furusawa-Nishii, E., Ito, K., Saito, Y., and Ogasawara, K. (2020). Point mutation bias in SARS-CoV-2 variants results in increased ability to stimulate inflammatory responses. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-74843-x"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wang, R., Chen, J., Gao, K., Hozumi, Y., Yin, C., and Wei, G.W. (2021). Analysis of SARS-CoV-2 mutations in the United States suggests presence of four substrains and novel variants. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-01754-6"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tomaszewski, T., DeVries, R.S., Dong, M., Bhatia, G., Norsworthy, M.D., Zheng, X., and Caetano-Anoll\u00e9s, G. (2020). New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release. Evol. Bioinform., 16.","DOI":"10.1177\/1176934320965149"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1038\/s41467-022-29104-y","article-title":"De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report","volume":"13","author":"Gandhi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1007\/s11845-020-02482-2","article-title":"La Remdesivir and COVID-19 infection, therapeutic benefits or unnecessary risks?","volume":"190","author":"Vitiello","year":"2021","journal-title":"Ir. J. Med. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Fischer, W., Eron, J.J., Holman, W., Cohen, M.S., Fang, L., Szewczyk, L.J., Sheahan, T.P., Baric, R., Mollan, K.R., and Wolfe, C.R. (2021). Molnupiravir, an Oral Antiviral Treatment for COVID-19. MedRxiv.","DOI":"10.1101\/2021.06.17.21258639"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mari, A., Roloff, T., Stange, M., S\u00f8gaard, K.K., Asllanaj, E., Tauriello, G., Alexander, L.T., Schweitzer, M., Leuzinger, K., and Gensch, A. (2021). Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance. Microorganisms, 9.","DOI":"10.3390\/microorganisms9051094"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"eabo0718","DOI":"10.1126\/scitranslmed.abo0718","article-title":"Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms","volume":"14","author":"Stevens","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3604","DOI":"10.1038\/s41467-024-47941-x","article-title":"Dynamic diversity of SARS-CoV-2 genetic mutations in a lung transplantation patient with persistent COVID-19","volume":"15","author":"Igari","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1126\/science.abf9302","article-title":"Prospective mapping of viral mutations that escape antibodies used to treat COVID-19","volume":"371","author":"Starr","year":"2021","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.medj.2023.08.001","article-title":"Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2","volume":"4","author":"Hirotsu","year":"2023","journal-title":"Med"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1021\/acscentsci.3c00538","article-title":"Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir","volume":"9","author":"Hu","year":"2023","journal-title":"ACS Cent. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1093\/cid\/ciad494","article-title":"Nirmatrelvir Resistance\u2014De Novo E166V\/L50V Mutations in an Immunocompromised Patient Treated with Prolonged Nirmatrelvir\/Ritonavir Monotherapy Leading to Clinical and Virological Treatment Failure\u2014A Case Report","volume":"78","author":"Zuckerman","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/s41586-023-06609-0","article-title":"Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir","volume":"622","author":"Duan","year":"2023","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"eadl4013","DOI":"10.1126\/sciadv.adl4013","article-title":"In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance","volume":"10","author":"Zhu","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41586-022-05514-2","article-title":"Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir","volume":"613","author":"Iketani","year":"2023","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"eadd7197","DOI":"10.1126\/sciadv.add7197","article-title":"Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system","volume":"8","author":"Zhou","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"eade8778","DOI":"10.1126\/sciadv.ade8778","article-title":"Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors","volume":"9","author":"Moghadasi","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1038\/s41467-023-40018-1","article-title":"In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir","volume":"14","author":"Kiso","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Ip, J.D., Wing-Ho Chu, A., Chan, W.M., Cheuk-Ying Leung, R., Umer Abdullah, S.M., Sun, Y., and Kai-Wang To, K. (2023). Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance. EBioMedicine, 91.","DOI":"10.1016\/j.ebiom.2023.104559"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Yamamoto, C., Taniguchi, M., Furukawa, K., Inaba, T., Niiyama, Y., Ide, D., Mizutani, S., Kuroda, J., Tanino, Y., and Nishioka, K. (2024). Nirmatrelvir Resistance in an Immunocompromised Patient with Persistent Coronavirus Disease 2019. Viruses, 16.","DOI":"10.3390\/v16050718"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1021\/acsinfecdis.3c00560","article-title":"Contributions of Hyperactive Mutations in Mpro from SARS-CoV-2 to Drug Resistance","volume":"10","author":"Flynn","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1126\/science.abi9310","article-title":"Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme","volume":"373","author":"Liu","year":"2021","journal-title":"Science"},{"key":"ref_61","unstructured":"(2025, April 22). WHO World Health Organization: Draft Landscape and Tracker of COVID-19 Candidate Vaccines. Available online: https:\/\/www.who.int\/publications\/m\/item\/draft-landscape-of-covid-19-candidate-vaccines."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"12878","DOI":"10.1073\/pnas.1717159115","article-title":"Why the evolution of vaccine resistance is less of a concern than the evolution of drug resistance","volume":"115","author":"Kennedy","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kennedy, D.A., Read, A.F., and Kennedy, D.A. (2020). Monitor for COVID-19 vaccine resistance evolution during clinical trials. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3001000"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/s41591-021-01318-5","article-title":"Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies","volume":"27","author":"Planas","year":"2021","journal-title":"Nat. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/s41591-021-01285-x","article-title":"SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma","volume":"27","author":"Wibmer","year":"2021","journal-title":"Nat. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/s41586-021-03471-w","article-title":"Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma","volume":"593","author":"Cele","year":"2021","journal-title":"Nature"},{"key":"ref_67","first-page":"10","article-title":"Novavax vaccine delivers 89% efficacy against COVID-19 in U.K.\u2014But is less potent in South Africa","volume":"12","author":"Wadman","year":"2021","journal-title":"Science"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/d41586-021-00268-9","article-title":"Novavax offers first evidence that COVID vaccines protect people against variants","volume":"590","author":"Callaway","year":"2021","journal-title":"Nature"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/S0140-6736(21)00183-5","article-title":"Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence","volume":"397","author":"Sabino","year":"2021","journal-title":"Lancet"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/s41586-021-03324-6","article-title":"mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants","volume":"592","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Tada, T., Dcosta, B.M., Samanovic-Golden, M., Herati, R.S., Cornelius, A., Mulligan, M.J., and Landau, N.R. (2021). Neutralization of viruses with European, South African, and United States SARS-CoV-2 variant spike proteins by convalescent sera and BNT162b2 mRNA vaccine-elicited antibodies. Biorxiv, 12.","DOI":"10.1101\/2021.02.05.430003"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41586-021-03291-y","article-title":"SARS-CoV-2 evolution during treatment of chronic infection","volume":"592","author":"Kemp","year":"2021","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1126\/science.abf6950","article-title":"Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape","volume":"371","author":"McCarthy","year":"2021","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"134322","DOI":"10.1016\/j.scitotenv.2019.134322","article-title":"Antiviral drugs in aquatic environment and wastewater treatment plants: A review on occurrence, fate, removal and ecotoxicity","volume":"699","author":"Nannou","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"(2020). The race against COVID-19. Nat. Nanotechnol., 15, 239\u2013240.","DOI":"10.1038\/s41565-020-0680-y"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/d41587-020-00003-1","article-title":"Coronavirus puts drug repurposing on the fast track","volume":"38","author":"Harrison","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"150380","DOI":"10.1016\/j.scitotenv.2021.150380","article-title":"Antiviral drug Umifenovir (Arbidol) in municipal wastewater during the COVID-19 pandemic: Estimated levels and transformation","volume":"805","author":"Kosyakov","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"12873","DOI":"10.1021\/es303203c","article-title":"Synchronous dynamics of observed and predicted values of anti-influenza drugs in environmental waters during a seasonal influenza outbreak","volume":"46","author":"Azuma","year":"2012","journal-title":"Environ. Sci. Technol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"8503","DOI":"10.1021\/acs.est.0c03105","article-title":"Potential Emergence of Antiviral-Resistant Pandemic Viruses via Environmental Drug Exposure of Animal Reservoirs","volume":"54","author":"Kumar","year":"2020","journal-title":"Environ. Sci. Technol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Lood, R., Ert\u00fcrk, G., and Mattiasson, B. (2017). Revisiting antibiotic resistance spreading in wastewater treatment plants\u2014Bacteriophages as a much neglected potential transmission vehicle. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.02298"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1126\/science.1122438","article-title":"Global patterns of influenza A virus in wild birds","volume":"312","author":"Olsen","year":"2006","journal-title":"Science"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Mackull\u2019ak, T., Cverenk\u00e1rov\u00e1, K., Sta\u0148ov\u00e1, A.V., Feh\u00e9r, M., Tam\u00e1\u0161, M., \u0160kulcov\u00e1, A.B., G\u00e1l, M., Naumowicz, M., \u0160palkov\u00e1, V., and B\u00edro\u0161ov\u00e1, L. (2021). Hospital wastewater\u2014Source of specific micropollutants, antibiotic-resistant microorganisms, viruses, and their elimination. Antibiotics, 10.","DOI":"10.3390\/antibiotics10091070"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"117400","DOI":"10.1016\/j.watres.2021.117400","article-title":"Wastewater surveillance of SARS-CoV-2 across 40 U.S. states from February to June 2020","volume":"202","author":"Wu","year":"2021","journal-title":"Water Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1016\/j.cub.2020.03.022","article-title":"Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak","volume":"30","author":"Zhang","year":"2020","journal-title":"Curr. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.tibtech.2019.09.009","article-title":"Next-Generation Sequencing: An Eye-Opener for the Surveillance of Antiviral Resistance in Influenza","volume":"38","author":"Saelens","year":"2020","journal-title":"Trends Biotechnol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"vew014","DOI":"10.1093\/ve\/vew014","article-title":"Antiviral drug resistance as an adaptive process","volume":"2","author":"Irwin","year":"2016","journal-title":"Virus Evol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.idc.2010.07.001","article-title":"Antiviral drug resistance: Mechanisms and clinical implications","volume":"24","author":"Strasfeld","year":"2010","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Melville, K., Rodriguez, T., and Dobrovolny, H.M. (2018). Investigating different mechanisms of action in combination therapy for influenza. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01207"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Miatmoko, A., Hendrianto, E., Karsari, D., Dinaryanti, A., Ertanti, N., Ihsan, I.S., Purnama, D.S., and Asmarawati, T.P. (2021). An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and\/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0252302"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1111\/bcp.15089","article-title":"Combination therapies for COVID-19: An overview of the clinical trials landscape","volume":"88","author":"Akinbolade","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"14857","DOI":"10.1073\/pnas.2009637117","article-title":"Identifying airborne transmission as the dominant route for the spread of COVID-19","volume":"117","author":"Zhang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S2468-1253(20)30158-8","article-title":"Wastewater monitoring of SARS-CoV-2: Lessons from illicit drug policy","volume":"5","author":"Lancaster","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.nutos.2024.11.002","article-title":"Beneficial effects of probiotics to flatten the curve of COVID-19 pandemic: A review","volume":"58","author":"Rabiei","year":"2024","journal-title":"Clin. Nutr. Open Sci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"100837","DOI":"10.1016\/j.nmni.2021.100837","article-title":"Oral probiotics in coronavirus disease 2019: Connecting the gut\u2013lung axis to viral pathogenesis, inflammation, secondary infection and clinical trials","volume":"40","author":"Baindara","year":"2021","journal-title":"New Microbes New Infect."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1080\/14712598.2020.1807001","article-title":"Host-directed therapies: A potential solution to combat COVID-19","volume":"20","author":"Baindara","year":"2020","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"100095","DOI":"10.1016\/j.imj.2024.100095","article-title":"Innovative applications of artificial intelligence during the COVID-19 pandemic","volume":"3","author":"Lv","year":"2024","journal-title":"Infect. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"veaa061","DOI":"10.1093\/ve\/veaa061","article-title":"Temporal signal and the phylodynamic threshold of SARS-CoV-2","volume":"6","author":"Duchene","year":"2020","journal-title":"Virus Evol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1099\/jgv.0.001453","article-title":"SARS-coronavirus-2 replication in Vero E6 cells: Replication kinetics, rapid adaptation and cytopathology","volume":"101","author":"Ogando","year":"2020","journal-title":"J. Gen. Virol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1126\/science.abc4730","article-title":"Adaptation of SARS-CoV-2 in BALB\/c mice for testing vaccine efficacy","volume":"369","author":"Gu","year":"2020","journal-title":"Science"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.cell.2020.09.050","article-title":"A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice","volume":"183","author":"Leist","year":"2020","journal-title":"Cell"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/5\/722\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:34:42Z","timestamp":1760031282000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/5\/722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,18]]},"references-count":100,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["v17050722"],"URL":"https:\/\/doi.org\/10.3390\/v17050722","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,18]]}}}