SARS-CoV-2 Remdesivir Exposure Leads to Different Evolutionary Pathways That Converge in Moderate Levels of Drug Resistance
Carlota Fernandez-Antunez, Line A Ryberg, Kuan Wang, Long V Pham, Lotte S Mikkelsen, Ulrik Fahnøe, Katrine T Hartmann, Henrik E Jensen, Kenn Holmbeck, Jens Bukh, Santseharay Ramirez
Viruses, doi:10.3390/v17081055
Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC 50 and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC 50 ). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0-to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/v17081055/s1 , Supporting Methods; Figure S1 : Antiviral activity of remdesivir, GS-441524, obeldesivir, and molnupiravir; Figure S2 : Competitive fitness of original and RDV escape viruses; Figure S3 : Neutralizing curves of hamster plasma samples; Figure S4 : Principal component analysis of nsp12-motif D in a nsp7-nsp8-nsp12 molecular dynamics simulation; Table S1 : Genotypic characterization of remdesivir resistance selection experiment-derived viruses; Table S2 : Genotypic characterization of mutant viruses; Table S3 : Histopathological analysis of animal lungs.
Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
References
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the Treatment of COVID-19-Final Report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764
Binderup, Galli, Fossat, Fernandez-Antunez, Mikkelsen et al., Differential activity of nucleotide analogs against tick-borne encephalitis and yellow fever viruses in human cell lines, Virology,
doi:10.1016/j.virol.2023.06.002
Checkmahomed, Carbonneau, Du Pont, Riola, Perry et al., In Vitro Selection of Remdesivir-Resistant SARS-CoV-2 Demonstrates High Barrier to Resistance, Antimicrob. Agents Chemother,
doi:10.1128/aac.00198-22
Cho, Saunders, Butler, Zhang, Xu et al., Synthesis and antiviral activity of a series of 1 ′ -substituted 4-aza-7,9-dideazaadenosine C-nucleosides, Bioorganic Med. Chem. Lett,
doi:10.1016/j.bmcl.2012.02.105
Cihlar, Mackman, Journey of remdesivir from the inhibition of hepatitis C virus to the treatment of COVID-19, Antivir. Ther,
doi:10.1177/13596535221082773
Fahnøe, Pham, Fernandez-Antunez, Costa, Rivera-Rangel et al., Versatile SARS-CoV-2 Reverse-Genetics Systems for the Study of Antiviral Resistance and Replication, Viruses,
doi:10.3390/v14020172
Fernandez-Antunez, Wang, Fahnøe, Mikkelsen, Gottwein et al., Characterization of multi-DAA resistance using a novel hepatitis C virus genotype 3a infectious culture system, Hepatology,
doi:10.1097/HEP.0000000000000353
Gallego, Sheldon, Moreno, Gregori, Quer et al., Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus, Antimicrob. Agents Chemother,
doi:10.1128/AAC.00581-16
Gammeltoft, Zhou, Duarte Hernandez, Galli, Offersgaard et al., Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro, Antimicrob. Agents Chemother,
doi:10.1128/AAC.02680-20
Gammeltoft, Zhou, Ryberg, Pham, Binderup et al., Substitutions in SARS-CoV-2 Mpro Selected by Protease Inhibitor Boceprevir Confer Resistance to Nirmatrelvir, Viruses,
doi:10.3390/v15091970
Gandhi, Klein, Robertson, Peña-Hernández, Lin et al., De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report, Nat. Commun,
doi:10.1038/s41467-022-29104-y
Gao, Yan, Huang, Liu, Zhao et al., Structure of the RNA-dependent RNA polymerase from COVID-19 virus, Science,
doi:10.1126/science.abb7498
Graepel, Lu, Case, Sexton, Smith et al., Proofreading-Deficient Coronaviruses Adapt for Increased Fitness over Long-Term Passage without Reversion of Exoribonuclease-Inactivating Mutations, mBio,
doi:10.1128/mBio.01503-17
Harvey, Carabelli, Jackson, Gupta, Thomson et al., SARS-CoV-2 variants, spike mutations and immune escape, Nat. Rev. Microbiol,
doi:10.1038/s41579-021-00573-0
Hedskog, Rodriguez, Roychoudhury, Huang, Jerome et al., Viral Resistance Analyses from the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1), J. Infect. Dis,
doi:10.1093/infdis/jiad270
Hedskog, Spinner, Protzer, Hoffmann, Ko et al., No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials, Viruses,
doi:10.3390/v16040546
Heyer, Günther, Robitaille, Lütgehetmann, Addo et al., Remdesivir-induced emergence of SARS-CoV2 variants in patients with prolonged infection, Cell Rep. Med,
doi:10.1016/j.xcrm.2022.100735
Hirotsu, Kobayashi, Kakizaki, Saito, Tsutsui et al., Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2, Med,
doi:10.1016/j.medj.2023.08.001
Hogan, Duerr, Dimartino, Marier, Hochman et al., Remdesivir Resistance in Transplant Recipients with Persistent Coronavirus Disease, Clin. Infect. Dis,
doi:10.1093/cid/ciac769
Igari, Sakao, Ishige, Saito, Murata et al., Dynamic diversity of SARS-CoV-2 genetic mutations in a lung transplantation patient with persistent COVID-19, Nat. Commun,
doi:10.1038/s41467-024-47941-x
Li, Cao, Li, Cong, Li et al., Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models, J. Med. Chem,
doi:10.1021/acs.jmedchem.0c01929
Ling-Hu, Simons, Rios-Guzman, Carvalho, Agnes et al., The impact of remdesivir on SARS-CoV-2 evolution in vivo, JCI Insight,
doi:10.1172/jci.insight.182376
Lo, Jordan, Arvey, Sudhamsu, Shrivastava-Ranjan et al., GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses, Sci. Rep,
doi:10.1038/srep43395
Lo, Kariv, Hao, Gammeltoft, Bukh et al., Replication capacity and susceptibility of nirmatrelvir-resistant mutants to next-generation Mpro inhibitors in a SARS-CoV-2 replicon system, Antivir. Res,
doi:10.1016/j.antiviral.2024.106022
Ma, Wu, Shaw, Gao, Wang et al., Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex, Proc. Natl. Acad. Sci
Mackman, Hui, Perron, Murakami, Palmiotti et al., Prodrugs of a 1 ′ -CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV, J. Med. Chem,
doi:10.1021/acs.jmedchem.1c00071
Mackman, Kalla, Babusis, Pitts, Barrett et al., Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys, J. Med. Chem,
doi:10.1021/acs.jmedchem.3c00750
Malone, Perry, Olinares, Lee, Chen et al., Structural basis for substrate selection by the SARS-CoV-2 replicase, Nature,
doi:10.1038/s41586-022-05664-3
Martinot, Jary, Fafi-Kremer, Leducq, Delagreverie et al., Emerging RNA-Dependent RNA Polymerase Mutation in a Remdesivir-Treated B-cell Immunodeficient Patient with Protracted Coronavirus Disease, Clin. Infect. Dis,
doi:10.1093/cid/ciaa1474
Mejer, Fahnøe, Galli, Ramirez, Weiland et al., Mutations Identified in the Hepatitis C Virus (HCV) Polymerase of Patients with Chronic HCV Treated with Ribavirin Cause Resistance and Affect Viral Replication Fidelity, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01417-20
Nooruzzaman, Johnson, Rani, Finkelsztein, Caserta et al., Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections, Nat. Commun,
doi:10.1038/s41467-024-51924-3
Offersgaard, Duarte Hernandez, Feng, Marichal-Gallardo, Holmbeck et al., An inactivated SARS-CoV-2 vaccine induced cross-neutralizing persisting antibodies and protected against challenge in small animals, iScience,
doi:10.1016/j.isci.2023.105949
Pawlotsky, Retreatment of Hepatitis C Virus-Infected Patients with Direct-Acting Antiviral Failures, Semin. Liver Dis,
doi:10.1055/s-0039-1687823
Pham, Underwood, Binderup, Fahnøe, Fernandez-Antunez et al., Neutralisation resistance of SARS-CoV-2 spike-variants is primarily mediated by synergistic receptor binding domain substitutions, Emerg. Microbes Infect,
doi:10.1080/22221751.2024.2412643
Pruijssers, George, Schäfer, Leist, Gralinksi et al., Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice, Cell Rep,
doi:10.1016/j.celrep.2020.107940
Ramirez, Fernandez-Antunez, Galli, Underwood, Pham et al., Overcoming Culture Restriction for SARS-CoV-2 in Human Cells Facilitates the Screening of Compounds Inhibiting Viral Replication, Antimicrob. Agents Chemother,
doi:10.1128/AAC.00097-21
Rodriguez, Lee, Li, Martin, Han et al., SARS-CoV-2 resistance analyses from the Phase 3 PINETREE study of remdesivir treatment in nonhospitalized participants, Antimicrob. Agents Chemother,
doi:10.1128/aac.01238-24
Sama, Selisko, Falcou, Fattorini, Piorkowski et al., The effects of Remdesivir's functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase, Antivir. Res,
doi:10.1016/j.antiviral.2024.106034
Schreiber, Rodner, Oberberg, Anhlan, Bletz et al., The host-targeted antiviral drug Zapnometinib exhibits a high barrier to the development of SARS-CoV-2 resistance, Antivir. Res,
doi:10.1016/j.antiviral.2024.105840
Shaw Research, Molecular Dynamics Simulations Related to SARS-CoV-2
Sheahan, Sims, Graham, Menachery, Gralinski et al., Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses, Sci. Transl. Med,
doi:10.1126/scitranslmed.aal3653
Smyk, Szydłowska, Szulc, Majewska, Evolution of Influenza Viruses-Drug Resistance, Treatment Options, and Prospects, Int. J. Mol. Sci,
doi:10.3390/ijms232012244
Stevens, Pruijssers, Lee, Gordon, Tchesnokov et al., Mutations in the SARS-CoV-2 RNA dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms, Sci. Transl. Med,
doi:10.1126/scitranslmed.abo0718
Sun, Xie, Bu, Zhong, Zeng, Molecular characteristics, immune evasion, and impact of SARS-CoV-2 variants, Signal Transduct. Target. Ther,
doi:10.1038/s41392-022-01039-2
Szemiel, Merits, Orton, Maclean, Pinto et al., In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2, PLoS Pathog,
doi:10.1371/journal.ppat.1009929
Tanimoto, Itoh, Okumura, Bucket brigade" using lysine residues in RNA-dependent RNA polymerase of SARS-CoV-2, Biophys. J,
doi:10.1016/j.bpj.2021.07.026
Tanino, Nishioka, Yamamoto, Watanabe, Daidoji et al., Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient, Infect. Drug Resist,
doi:10.2147/IDR.S438915
Torii, Kim, Koseki, Suzuki, Iwanami et al., Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir, PLoS Pathog,
doi:10.1371/journal.ppat.1011231
Truong, Ryutov, Pandey, Yee, Goldberg et al., Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: A consecutive case series, EBioMedicine,
doi:10.1016/j.ebiom.2021.103355
Underwood, Sølund, Fernandez-Antunez, Villadsen, Winckelmann et al., Neutralisation titres against SARS-CoV-2 are sustained 6 months after onset of symptoms in individuals with mild COVID-19, EBioMedicine,
doi:10.1016/j.ebiom.2021.103519
Warren, Jordan, Lo, Ray, Mackman et al., Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys, Nature,
doi:10.1038/nature17180
Williamson, Feldmann, Schwarz, Meade-White, Porter et al., Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2, Nature,
doi:10.1038/s41586-020-2423-5
Yang, Multani, Garrigues, Oh, Hemarajata et al., Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation, Microorganisms,
doi:10.3390/microorganisms11082096
Zhou, Gammeltoft, Ryberg, Pham, Tjørnelund et al., Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Sci. Adv,
doi:10.1126/sciadv.add7197
Zhou, Gilmore, Ramirez, Settels, Gammeltoft et al., In vitro efficacy of artemisinin-based treatments against SARS-CoV-2, Sci. Rep,
doi:10.1038/s41598-021-93361-y
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"abstract": "<jats:p>Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC50 and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC50). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1-fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0- to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance.</jats:p>",
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"DOI": "10.1021/acs.jmedchem.1c00071",
"article-title": "Prodrugs of a 1′-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV",
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"article-title": "Differential activity of nucleotide analogs against tick-borne encephalitis and yellow fever viruses in human cell lines",
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"DOI": "10.1126/scitranslmed.aal3653",
"article-title": "Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses",
"author": "Sheahan",
"doi-asserted-by": "crossref",
"first-page": "eaal3653",
"journal-title": "Sci. Transl. Med.",
"key": "ref_7",
"volume": "9",
"year": "2017"
},
{
"DOI": "10.1016/j.celrep.2020.107940",
"article-title": "Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice",
"author": "Pruijssers",
"doi-asserted-by": "crossref",
"first-page": "107940",
"journal-title": "Cell Rep.",
"key": "ref_8",
"volume": "32",
"year": "2020"
},
{
"DOI": "10.1038/s41586-020-2423-5",
"article-title": "Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2",
"author": "Williamson",
"doi-asserted-by": "crossref",
"first-page": "273",
"journal-title": "Nature",
"key": "ref_9",
"volume": "585",
"year": "2020"
},
{
"DOI": "10.1128/AAC.00097-21",
"article-title": "Overcoming Culture Restriction for SARS-CoV-2 in Human Cells Facilitates the Screening of Compounds Inhibiting Viral Replication",
"author": "Ramirez",
"doi-asserted-by": "crossref",
"first-page": "e0009721",
"journal-title": "Antimicrob. Agents Chemother.",
"key": "ref_10",
"volume": "65",
"year": "2021"
},
{
"DOI": "10.1056/NEJMoa2007764",
"article-title": "Remdesivir for the Treatment of COVID-19—Final Report",
"author": "Beigel",
"doi-asserted-by": "crossref",
"first-page": "1813",
"journal-title": "N. Engl. J. Med.",
"key": "ref_11",
"volume": "383",
"year": "2020"
},
{
"key": "ref_12",
"unstructured": "WHO Solidarity Trial Consortium (2022). Remdesivir and three other drugs for hospitalised patients with COVID-19: Final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet, 399, 1941–1953."
},
{
"DOI": "10.1007/s40121-023-00900-3",
"article-title": "Remdesivir for the Treatment of COVID-19: A Narrative Review",
"author": "Godwin",
"doi-asserted-by": "crossref",
"first-page": "1",
"journal-title": "Infect. Dis. Ther.",
"key": "ref_13",
"volume": "13",
"year": "2024"
},
{
"key": "ref_14",
"unstructured": "EMA (European Medicines Agency) (2025, July 03). Authorised COVID-19 Treatments n.d. Available online: https://www.ema.europa.eu/en/human-regulatory-overview/public-health-threats/coronavirus-disease-covid-19/covid-19-medicines."
},
{
"key": "ref_15",
"unstructured": "FDA (US Food and Drug Administration) (2025, July 03). Coronavirus (COVID-19)|Drugs. n.d, Available online: https://www.fda.gov/drugs/emergency-preparedness-drugs/coronavirus-covid-19-drugs."
},
{
"DOI": "10.1038/s41579-021-00573-0",
"article-title": "SARS-CoV-2 variants, spike mutations and immune escape",
"author": "Harvey",
"doi-asserted-by": "crossref",
"first-page": "409",
"journal-title": "Nat. Rev. Microbiol.",
"key": "ref_16",
"volume": "19",
"year": "2021"
},
{
"DOI": "10.1055/s-0039-1687823",
"article-title": "Retreatment of Hepatitis C Virus-Infected Patients with Direct-Acting Antiviral Failures",
"author": "Pawlotsky",
"doi-asserted-by": "crossref",
"first-page": "354",
"journal-title": "Semin. Liver Dis.",
"key": "ref_17",
"volume": "39",
"year": "2019"
},
{
"DOI": "10.1016/j.chom.2019.06.010",
"article-title": "The Impact of HIV-1 Drug Escape on the Global Treatment Landscape",
"author": "Collier",
"doi-asserted-by": "crossref",
"first-page": "48",
"journal-title": "Cell Host Microbe",
"key": "ref_18",
"volume": "26",
"year": "2019"
},
{
"DOI": "10.3390/ijms232012244",
"doi-asserted-by": "crossref",
"key": "ref_19",
"unstructured": "Smyk, J.M., Szydłowska, N., Szulc, W., and Majewska, A. (2022). Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects. Int. J. Mol. Sci., 23."
},
{
"DOI": "10.1126/sciadv.add7197",
"article-title": "Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system",
"author": "Zhou",
"doi-asserted-by": "crossref",
"first-page": "eadd7197",
"journal-title": "Sci. Adv.",
"key": "ref_20",
"volume": "8",
"year": "2022"
},
{
"DOI": "10.1093/infdis/jiad270",
"article-title": "Viral Resistance Analyses from the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1)",
"author": "Hedskog",
"doi-asserted-by": "crossref",
"first-page": "1263",
"journal-title": "J. Infect. Dis.",
"key": "ref_21",
"volume": "228",
"year": "2023"
},
{
"DOI": "10.3390/v16040546",
"doi-asserted-by": "crossref",
"key": "ref_22",
"unstructured": "Hedskog, C., Spinner, C.D., Protzer, U., Hoffmann, D., Ko, C., Gottlieb, R.L., Askar, M., Roestenberg, M., de Vries, J.J., and Carbo, E.C. (2024). No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials. Viruses, 16."
},
{
"DOI": "10.1128/aac.01238-24",
"article-title": "SARS-CoV-2 resistance analyses from the Phase 3 PINETREE study of remdesivir treatment in nonhospitalized participants",
"author": "Rodriguez",
"doi-asserted-by": "crossref",
"first-page": "e01238-24",
"journal-title": "Antimicrob. Agents Chemother.",
"key": "ref_23",
"volume": "69",
"year": "2024"
},
{
"DOI": "10.3390/microorganisms11082096",
"doi-asserted-by": "crossref",
"key": "ref_24",
"unstructured": "Yang, S., Multani, A., Garrigues, J.M., Oh, M.S., Hemarajata, P., Burleson, T., Green, N.M., Oliai, C., Gaynor, P.T., and Beaird, O.E. (2023). Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation. Microorganisms, 11."
},
{
"DOI": "10.1016/j.xcrm.2022.100735",
"article-title": "Remdesivir-induced emergence of SARS-CoV2 variants in patients with prolonged infection",
"author": "Heyer",
"doi-asserted-by": "crossref",
"first-page": "100735",
"journal-title": "Cell Rep. Med.",
"key": "ref_25",
"volume": "3",
"year": "2022"
},
{
"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",
"author": "Hirotsu",
"doi-asserted-by": "crossref",
"first-page": "813",
"journal-title": "Med",
"key": "ref_26",
"volume": "4",
"year": "2023"
},
{
"DOI": "10.1093/cid/ciaa1474",
"article-title": "Emerging RNA-Dependent RNA Polymerase Mutation in a Remdesivir-Treated B-cell Immunodeficient Patient with Protracted Coronavirus Disease 2019",
"author": "Martinot",
"doi-asserted-by": "crossref",
"first-page": "e1762",
"journal-title": "Clin. Infect. Dis.",
"key": "ref_27",
"volume": "73",
"year": "2021"
},
{
"DOI": "10.2147/IDR.S438915",
"article-title": "Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient",
"author": "Tanino",
"doi-asserted-by": "crossref",
"first-page": "531",
"journal-title": "Infect. Drug Resist.",
"key": "ref_28",
"volume": "17",
"year": "2024"
},
{
"DOI": "10.1093/cid/ciac769",
"article-title": "Remdesivir Resistance in Transplant Recipients with Persistent Coronavirus Disease 2019",
"author": "Hogan",
"doi-asserted-by": "crossref",
"first-page": "342",
"journal-title": "Clin. Infect. Dis.",
"key": "ref_29",
"volume": "76",
"year": "2023"
},
{
"DOI": "10.1038/s41467-024-51924-3",
"article-title": "Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections",
"author": "Nooruzzaman",
"doi-asserted-by": "crossref",
"first-page": "7999",
"journal-title": "Nat. Commun.",
"key": "ref_30",
"volume": "15",
"year": "2024"
},
{
"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",
"author": "Igari",
"doi-asserted-by": "crossref",
"first-page": "3604",
"journal-title": "Nat. Commun.",
"key": "ref_31",
"volume": "15",
"year": "2024"
},
{
"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",
"author": "Gandhi",
"doi-asserted-by": "crossref",
"first-page": "1547",
"journal-title": "Nat. Commun.",
"key": "ref_32",
"volume": "13",
"year": "2022"
},
{
"DOI": "10.1001/jamanetworkopen.2024.35431",
"article-title": "Emerging SARS-CoV-2 Resistance After Antiviral Treatment",
"author": "Tamura",
"doi-asserted-by": "crossref",
"first-page": "e2435431",
"journal-title": "JAMA Netw. Open",
"key": "ref_33",
"volume": "7",
"year": "2024"
},
{
"DOI": "10.1128/aac.00198-22",
"article-title": "In Vitro Selection of Remdesivir-Resistant SARS-CoV-2 Demonstrates High Barrier to Resistance",
"author": "Checkmahomed",
"doi-asserted-by": "crossref",
"first-page": "e00198-22",
"journal-title": "Antimicrob. Agents Chemother.",
"key": "ref_34",
"volume": "66",
"year": "2022"
},
{
"DOI": "10.1371/journal.ppat.1011231",
"doi-asserted-by": "crossref",
"key": "ref_35",
"unstructured": "Torii, S., Kim, K.S., Koseki, J., Suzuki, R., Iwanami, S., Fujita, Y., Jeong, Y.D., Ito, J., Asakura, H., and Nagashima, M. (2023). Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir. PLoS Pathog., 19."
},
{
"DOI": "10.1126/scitranslmed.abo0718",
"article-title": "Mutations in the SARS-CoV-2 RNA dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms",
"author": "Stevens",
"doi-asserted-by": "crossref",
"first-page": "eabo0718",
"journal-title": "Sci. Transl. Med.",
"key": "ref_36",
"volume": "14",
"year": "2022"
},
{
"DOI": "10.1371/journal.ppat.1009929",
"doi-asserted-by": "crossref",
"key": "ref_37",
"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": "10.1016/j.antiviral.2024.106034",
"article-title": "The effects of Remdesivir’s functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase",
"author": "Sama",
"doi-asserted-by": "crossref",
"first-page": "106034",
"journal-title": "Antivir. Res.",
"key": "ref_38",
"volume": "232",
"year": "2024"
},
{
"DOI": "10.1016/j.antiviral.2024.105840",
"article-title": "The host-targeted antiviral drug Zapnometinib exhibits a high barrier to the development of SARS-CoV-2 resistance",
"author": "Schreiber",
"doi-asserted-by": "crossref",
"first-page": "105840",
"journal-title": "Antivir. Res.",
"key": "ref_39",
"volume": "225",
"year": "2024"
},
{
"DOI": "10.3390/v15091970",
"doi-asserted-by": "crossref",
"key": "ref_40",
"unstructured": "Gammeltoft, K.A., Zhou, Y., Ryberg, L.A., Pham, L.V., Binderup, A., Hernandez, C.R.D., Offersgaard, A., Fahnøe, U., Peters, G.H., and Ramirez, S. (2023). Substitutions in SARS-CoV-2 Mpro Selected by Protease Inhibitor Boceprevir Confer Resistance to Nirmatrelvir. Viruses, 15."
},
{
"DOI": "10.1038/s41598-021-93361-y",
"doi-asserted-by": "crossref",
"key": "ref_41",
"unstructured": "Zhou, Y., Gilmore, K., Ramirez, S., Settels, E., Gammeltoft, K.A., Pham, L.V., Fahnøe, U., Feng, S., Offersgaard, A., and Trimpert, J. (2021). In vitro efficacy of artemisinin-based treatments against SARS-CoV-2. Sci. Rep., 11."
},
{
"DOI": "10.3390/v14020172",
"doi-asserted-by": "crossref",
"key": "ref_42",
"unstructured": "Fahnøe, U., Pham, L.V., Fernandez-Antunez, C., Costa, R., Rivera-Rangel, L.R., Galli, A., Feng, S., Mikkelsen, L.S., Gottwein, J.M., and Scheel, T.K. (2022). Versatile SARS-CoV-2 Reverse-Genetics Systems for the Study of Antiviral Resistance and Replication. Viruses, 14."
},
{
"DOI": "10.1080/22221751.2024.2412643",
"article-title": "Neutralisation resistance of SARS-CoV-2 spike-variants is primarily mediated by synergistic receptor binding domain substitutions",
"author": "Pham",
"doi-asserted-by": "crossref",
"first-page": "2412643",
"journal-title": "Emerg. Microbes Infect.",
"key": "ref_43",
"volume": "13",
"year": "2024"
},
{
"DOI": "10.1093/oxfordjournals.aje.a118408",
"article-title": "A simple method of estimating fifty per cent endpoints",
"author": "Reed",
"doi-asserted-by": "crossref",
"first-page": "493",
"journal-title": "Am. J. Epidemiol.",
"key": "ref_44",
"volume": "27",
"year": "1938"
},
{
"DOI": "10.1128/AAC.02680-20",
"article-title": "Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro",
"author": "Gammeltoft",
"doi-asserted-by": "crossref",
"first-page": "e02680-20",
"journal-title": "Antimicrob. Agents Chemother.",
"key": "ref_45",
"volume": "65",
"year": "2021"
},
{
"DOI": "10.1016/j.isci.2023.105949",
"article-title": "An inactivated SARS-CoV-2 vaccine induced cross-neutralizing persisting antibodies and protected against challenge in small animals",
"author": "Offersgaard",
"doi-asserted-by": "crossref",
"first-page": "105949",
"journal-title": "iScience",
"key": "ref_46",
"volume": "26",
"year": "2023"
},
{
"DOI": "10.1016/j.ebiom.2021.103519",
"doi-asserted-by": "crossref",
"key": "ref_47",
"unstructured": "Underwood, A.P., Sølund, C., Fernandez-Antunez, C., Villadsen, S.L., Winckelmann, A.A., Bollerup, S., Mikkelsen, L.S., Sørensen, A.-L., Feng, S., and Fahnøe, U. (2021). Neutralisation titres against SARS-CoV-2 are sustained 6 months after onset of symptoms in individuals with mild COVID-19. EBioMedicine, 71."
},
{
"DOI": "10.1128/AAC.01417-20",
"article-title": "Mutations Identified in the Hepatitis C Virus (HCV) Polymerase of Patients with Chronic HCV Treated with Ribavirin Cause Resistance and Affect Viral Replication Fidelity",
"author": "Mejer",
"doi-asserted-by": "crossref",
"first-page": "e01417-20",
"journal-title": "Antimicrob. Agents Chemother.",
"key": "ref_48",
"volume": "64",
"year": "2020"
},
{
"key": "ref_49",
"unstructured": "(The PyMOL Molecular Graphics System, 2021). The PyMOL Molecular Graphics System, Version 2.5.0."
},
{
"DOI": "10.1038/s41586-022-05664-3",
"article-title": "Structural basis for substrate selection by the SARS-CoV-2 replicase",
"author": "Malone",
"doi-asserted-by": "crossref",
"first-page": "781",
"journal-title": "Nature",
"key": "ref_50",
"volume": "614",
"year": "2023"
},
{
"DOI": "10.1126/science.abb7498",
"article-title": "Structure of the RNA-dependent RNA polymerase from COVID-19 virus",
"author": "Gao",
"doi-asserted-by": "crossref",
"first-page": "779",
"journal-title": "Science",
"key": "ref_51",
"volume": "368",
"year": "2020"
},
{
"key": "ref_52",
"unstructured": "D.E. Shaw Research (2021, January 22). Molecular Dynamics Simulations Related to SARS-CoV-2. D.E. Shaw Research Technical Data. Available online: https://www.deshawresearch.com/downloads/download_trajectory_sarscov2.cgi/."
},
{
"DOI": "10.1093/bioinformatics/btr168",
"article-title": "ProDy: Protein Dynamics Inferred from Theory and Experiments",
"author": "Bakan",
"doi-asserted-by": "crossref",
"first-page": "1575",
"journal-title": "Bioinformatics",
"key": "ref_53",
"volume": "27",
"year": "2011"
},
{
"DOI": "10.1016/0263-7855(96)00018-5",
"article-title": "VMD: Visual molecular dynamics",
"author": "Humphrey",
"doi-asserted-by": "crossref",
"first-page": "33",
"journal-title": "J. Mol. Graph.",
"key": "ref_54",
"volume": "14",
"year": "1996"
},
{
"DOI": "10.1021/acs.jmedchem.0c01929",
"article-title": "Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models",
"author": "Li",
"doi-asserted-by": "crossref",
"first-page": "2785",
"journal-title": "J. Med. Chem.",
"key": "ref_55",
"volume": "65",
"year": "2022"
},
{
"DOI": "10.1021/acs.jmedchem.3c00750",
"article-title": "Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys",
"author": "Mackman",
"doi-asserted-by": "crossref",
"first-page": "11701",
"journal-title": "J. Med. Chem.",
"key": "ref_56",
"volume": "66",
"year": "2023"
},
{
"article-title": "Structural Basis of SARS-CoV-2 Polymerase Inhibition by Favipiravir",
"author": "Peng",
"first-page": "100080",
"journal-title": "Innovation",
"key": "ref_57",
"volume": "2",
"year": "2021"
},
{
"DOI": "10.1016/j.bpj.2021.07.026",
"article-title": "“Bucket brigade” using lysine residues in RNA-dependent RNA polymerase of SARS-CoV-2",
"author": "Tanimoto",
"doi-asserted-by": "crossref",
"first-page": "3615",
"journal-title": "Biophys. J.",
"key": "ref_58",
"volume": "120",
"year": "2021"
},
{
"DOI": "10.1016/j.ebiom.2021.103355",
"doi-asserted-by": "crossref",
"key": "ref_59",
"unstructured": "Truong, T.T., Ryutov, A., Pandey, U., Yee, R., Goldberg, L., Bhojwani, D., Aguayo-Hiraldo, P., Pinsky, B.A., Pekosz, A., and Shen, L. (2021). Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: A consecutive case series. EBioMedicine, 67."
},
{
"DOI": "10.1128/AAC.00581-16",
"article-title": "Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus",
"author": "Gallego",
"doi-asserted-by": "crossref",
"first-page": "3786",
"journal-title": "Antimicrob. Agents Chemother.",
"key": "ref_60",
"volume": "60",
"year": "2016"
},
{
"DOI": "10.1097/HEP.0000000000000353",
"article-title": "Characterization of multi-DAA resistance using a novel hepatitis C virus genotype 3a infectious culture system",
"author": "Wang",
"doi-asserted-by": "crossref",
"first-page": "621",
"journal-title": "Hepatology",
"key": "ref_61",
"volume": "78",
"year": "2023"
},
{
"DOI": "10.1128/mBio.01503-17",
"article-title": "Proofreading-Deficient Coronaviruses Adapt for Increased Fitness over Long-Term Passage without Reversion of Exoribonuclease-Inactivating Mutations",
"author": "Graepel",
"doi-asserted-by": "crossref",
"first-page": "e01503-17",
"journal-title": "mBio",
"key": "ref_62",
"volume": "8",
"year": "2017"
},
{
"DOI": "10.1038/s41392-022-01039-2",
"article-title": "Molecular characteristics, immune evasion, and impact of SARS-CoV-2 variants",
"author": "Sun",
"doi-asserted-by": "crossref",
"first-page": "202",
"journal-title": "Signal Transduct. Target. Ther.",
"key": "ref_63",
"volume": "7",
"year": "2022"
},
{
"DOI": "10.1172/jci.insight.182376",
"article-title": "The impact of remdesivir on SARS-CoV-2 evolution in vivo",
"author": "Simons",
"doi-asserted-by": "crossref",
"first-page": "e182376",
"journal-title": "JCI Insight",
"key": "ref_64",
"volume": "10",
"year": "2025"
},
{
"DOI": "10.1016/j.antiviral.2024.106022",
"article-title": "Replication capacity and susceptibility of nirmatrelvir-resistant mutants to next-generation Mpro inhibitors in a SARS-CoV-2 replicon system",
"author": "Lo",
"doi-asserted-by": "crossref",
"first-page": "106022",
"journal-title": "Antivir. Res.",
"key": "ref_65",
"volume": "231",
"year": "2024"
},
{
"DOI": "10.1016/j.antiviral.2022.105501",
"article-title": "Kill or corrupt: Mechanisms of action and drug-resistance of nucleotide analogues against SARS-CoV-2",
"author": "Shannon",
"doi-asserted-by": "crossref",
"first-page": "105501",
"journal-title": "Antivir. Res.",
"key": "ref_66",
"volume": "210",
"year": "2023"
},
{
"DOI": "10.1073/pnas.1508686112",
"article-title": "Structural basis and functional analysis of the SARS coronavirus nsp14–nsp10 complex",
"author": "Ma",
"doi-asserted-by": "crossref",
"first-page": "9436",
"journal-title": "Proc. Natl. Acad. Sci. USA",
"key": "ref_67",
"volume": "112",
"year": "2015"
}
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"title": "SARS-CoV-2 Remdesivir Exposure Leads to Different Evolutionary Pathways That Converge in Moderate Levels of Drug Resistance",
"type": "journal-article",
"volume": "17"
}