Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity
Ikbel Hadj Hassine, Manel Ben M’hadheb, Luis Menéndez-Arias
Viruses, doi:10.3390/v14040841
In RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use of mutagens, driving viral populations to extinction. Extinction catastrophe can be experimentally induced by promutagenic nucleosides in cell culture models. The loss of HIV infectivity has been observed after passage in 5-hydroxydeoxycytidine or 5,6-dihydro-5-aza-2 -deoxycytidine while producing a two-fold increase in the viral mutation frequency. Among approved nucleoside analogs, experiments with polioviruses and other RNA viruses suggested that ribavirin can be mutagenic, although its mechanism of action is not clear. Favipiravir and molnupiravir exert an antiviral effect through lethal mutagenesis. Both drugs are broad-spectrum antiviral agents active against RNA viruses. Favipiravir incorporates into viral RNA, affecting the G→A and C→U transition rates. Molnupiravir (a prodrug of β-D-N 4 -hydroxycytidine) has been recently approved for the treatment of SARS-CoV-2 infection. Its triphosphate derivative can be incorporated into viral RNA and extended by the coronavirus RNA polymerase. Incorrect base pairing and inefficient extension by the polymerase promote mutagenesis by increasing the G→A and C→U transition frequencies. Despite having remarkable antiviral action and resilience to drug resistance, carcinogenic risks and genotoxicity are important concerns limiting their extended use in antiviral therapy.
Conflicts of Interest: The authors declare no conflict 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
Abdelnabi, Foo, De Jonghe, Maes, Weynand et al., Molnupiravir inhibits replication of the emerging SARS-CoV-2 variants of concern in a hamster infection model, J. Infect. Dis,
doi:10.1093/infdis/jiab361Abdelnabi, Foo, Kaptein, Zhang, Do et al., The combined treatment of molnupiravir and favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model, EBioMedicine,
doi:10.1016/j.ebiom.2021.103595Agostini, Pruijssers, Chappell, Gribble, Lu et al., Small-molecule antiviral β-D-N 4 -hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance, J. Virol,
doi:10.1128/JVI.01348-19Agudo, Ferrer-Orta, Arias, De La Higuera, Perales et al., A multi-step process of viral adaptation to a mutagenic nucleoside analogue by modulation of transition types leads to extinction-escape, PLoS Pathog,
doi:10.1371/journal.ppat.1001072Airaksinen, Pariente, Menéndez-Arias, Domingo, Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis, Virology,
doi:10.1016/S0042-6822(03)00144-2Arias, Thorne, Goodfellow, Favipiravir elicits antiviral mutagenesis during virus replication in vivo, Elife,
doi:10.7554/eLife.03679Arnold, Cameron, Poliovirus RNA-dependent RNA polymerase (3Dpol) is sufficient for template switching in vitro, J. Biol. Chem,
doi:10.1074/jbc.274.5.2706Baranovich, Wong, Armstrong, Marjuki, Webby et al., T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro, J. Virol,
doi:10.1128/JVI.02346-12Barrioluengo, Alvarez, Barbieri, Menéndez-Arias, Thermostable HIV-1 group O reverse transcriptase variants with the same fidelity as murine leukaemia virus reverse transcriptase, Biochem. J,
doi:10.1042/BJ20101852Bassi, Sempere, Meyn, Polacek, Arias, Extinction of Zika virus and Usutu virus by lethal mutagenesis reveals different patterns of sensitivity to three mutagenic drugs, Antimicrob. Agents Chemother,
doi:10.1128/AAC.00380-18Beach, Rawson, Kim, Patterson, Mansky, Novel inhibitors of human immunodeficiency virus type 2 infectivity, J. Gen. Virol,
doi:10.1099/vir.0.069864-0Bernal, Gomes Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients, N. Engl. J. Med,
doi:10.1056/NEJMoa2116044Borrego, De Ávila, Domingo, Brun, Lethal mutagenesis of Rift Valley fever virus induced by favipiravir, Antimicrob. Agents Chemother,
doi:10.1128/AAC.00669-19Cao, Wang, Xi, Zhang, Wang et al., PIG-A gene mutation as a genotoxicity biomarker in human population studies: An investigation in lead-exposed workers, Environ. Mol. Mutagen
Cases-González, Gutiérrez-Rivas, Menéndez-Arias, Coupling ribose selection to fidelity of DNA synthesis: The role of Tyr-115 of human immunodeficiency virus type 1 reverse transcriptase, J. Biol. Chem,
doi:10.1074/jbc.M910361199Chung, Sun, Parker, Arterburn, Bartolucci et al., Ribavirin reveals a lethal threshold of allowable mutation frequency for Hantaan virus, J. Virol,
doi:10.1128/JVI.00874-07Clouser, Patterson, Mansky, Exploiting drug repositioning for discovery of a novel HIV combination therapy, J. Virol,
doi:10.1128/JVI.01006-10Coffin, HIV population dynamics in vivo: Implications for genetic variation, pathogenesis, and therapy, Science,
doi:10.1126/science.7824947Contreras, Hiasa, He, Terella, Schmidt et al., Viral RNA mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system, J. Virol,
doi:10.1128/JVI.76.17.8505-8517.2002Cox, Wolf, Plemper, Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets, Nat. Microbiol,
doi:10.1038/s41564-020-00835-2Crotty, Maag, Arnold, Zhong, Lau et al., The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen, Nat. Med,
doi:10.1038/82191Cuevas, González-Candelas, Moya, Sanjuán, Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo, J. Virol,
doi:10.1128/JVI.00201-09Dapp, Clouser, Patterson, Mansky, 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1, J. Virol,
doi:10.1128/JVI.01406-09De Avila, Moreno, Perales, Domingo, Favipiravir can evoke lethal mutagenesis and extinction of foot-and-mouth disease virus, Virus Res,
doi:10.1016/j.virusres.2017.03.014Delang, Segura Guerrero, Tas, Quérat, Pastorino et al., Mutations in the Chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broadspectrum antiviral, J. Antimicrob. Chemother,
doi:10.1093/jac/dku209Dietz, Schelhorn, Fitting, Mihm, Susser et al., Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients, J. Virol,
doi:10.1128/JVI.02778-12Drake, Charlesworth, Charlesworth, Crow, Rates of spontaneous mutation, Genetics
Díaz-Martínez, Brichette-Mieg, Pineño-Ramos, Domínguez-Huerta, Grande-Pérez, Lethal mutagenesis of an RNA plant virus via lethal defection, Sci. Rep,
doi:10.1038/s41598-018-19829-6Eckerle, Becker, Halpin, Li, Venter et al., Infidelity of SARS-CoV nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing, PLoS Pathog,
doi:10.1371/journal.ppat.1000896Eckerle, Lu, Sperry, Choi, Denison, High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants, J. Virol,
doi:10.1128/JVI.01296-07Eigen, From Strange Simplicity to Complex Familiarity: A Treatise on Matter, Information, Life and Thought
Eron, Jr, Holman, Cohen, Fang et al., A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus, Sci. Transl. Med,
doi:10.1126/scitranslmed.abl7430Escribano-Romero, Jiménez De Oya, Domingo, Saiz, Extinction of West Nile virus by favipiravir through lethal mutagenesis, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01400-17Espy, Nagle, Pfeffer, Garcia, Chitty et al., T-705 induces lethal mutagenesis in Ebola and Marburg populations in macaques, Antiviral. Res,
doi:10.1016/j.antiviral.2019.06.001Ferrer-Orta, Sierra, Agudo, De La Higuera, Arias et al., Structure of foot-and-mouth disease virus mutant polymerases with reduced sensitivity to ribavirin, J. Virol,
doi:10.1128/JVI.02420-09Fischer, None
Gallego, Gregori, Soria, García-Crespo, García-Álvarez et al., Resistance of high fitness hepatitis C virus to lethal mutagenesis, Virology,
doi:10.1016/j.virol.2018.07.030Gallego, Soria, Gregori, De Ávila, García-Crespo et al., Synergistic lethal mutagenesis of hepatitis C virus, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01653-19Geraghty, Aliota, Bonnac, Broad-spectrum antiviral strategies and nucleoside analogues, Viruses
Gohara, Crotty, Arnold, Yoder, Andino et al., Poliovirus RNA-dependent RNA polymerase (3Dpol): Structural, biochemical, and biological analysis of conserved structural motifs a and b, J. Biol. Chem,
doi:10.1074/jbc.M002671200Goldhill, Yan, Frise, Zhou, Shelley et al., Favipiravir-resistant influenza A virus shows potential for transmission, PLoS Pathog,
doi:10.1371/journal.ppat.1008937Gong, Peersen, Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.1007626107Gordon, Tchesnokov, Schinazi, Götte, Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template, J. Biol. Chem,
doi:10.1016/j.jbc.2021.100770Graci, Cameron, Mechanisms of action of ribavirin against distinct viruses, Rev. Med. Virol,
doi:10.1002/rmv.483Graci, Gnädig, Galarraga, Castro, Vignuzzi et al., Mutational robustness of an RNA virus influences sensitivity to lethal mutagenesis, J. Virol,
doi:10.1128/JVI.05712-11Graci, Harki, Korneeva, Edathil, Too et al., Lethal mutagenesis of poliovirus mediated by a mutagenic pyrimidine analogue, J. Virol,
doi:10.1128/JVI.01028-07Graci, Too, Smidansky, Edathil, Barr et al., Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01056-07Grande-Pérez, Lázaro, Lowenstein, Domingo, Manrubia, Suppression of viral infectivity through lethal defection, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.0408871102Harki, Graci, Galarraga, Chain, Cameron et al., Synthesis and antiviral activity of 5-substituted cytidine analogues: Identification of a potent inhibitor of viral RNA-dependent RNA polymerases, J. Med. Chem,
doi:10.1021/jm060872xHaruna, Spiegelman, Specific template requirments of RNA replicases
Holland, Domingo, De La Torre, Steinhauer, Mutation frequencies at defined single codon sites in vesicular stomatitis virus and poliovirus can be increased only slightly by chemical mutagenesis, J. Virol,
doi:10.1128/jvi.64.8.3960-3962.1990Jena, Role of different tautomers in the base-pairing abilities of some of the vital antiviral drugs used against COVID-19, Phys. Chem. Chem. Phys,
doi:10.1039/D0CP05297CJin, Smith, Rajwanshi, Kim, Deval, The ambiguous base-pairing and high substrate efficiency of T-705 (favipiravir) ribofuranosyl 5'-triphosphate towards influenza A virus polymerase, PLoS ONE,
doi:10.1371/journal.pone.0068347Jordan, Stevens, Deval, Nucleosides for the treatment of respiratory RNA virus infections, Antivir. Chem. Chemother,
doi:10.1177/2040206618764483Kabinger, Stiller, Schmitzová, Dienemann, Kokic et al., Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis, Nat. Struct. Mol. Biol,
doi:10.1038/s41594-021-00651-0Kentsis, Topisirovic, Culjkovic, Shao, Borden, Ribavirin suppresses EIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.0406927102Köppe, Menéndez-Arias, Oroszlan, Expression and purification of the mouse mammary tumor virus gag-pro transframe protein p30 and characterization of its dUTPase activity, J. Virol,
doi:10.1128/jvi.68.4.2313-2319.1994Lacasse, Remington, North, The mutation frequency of feline immunodeficiency virus enhanced by 3 -azido-3 -deoxythymidine, J. Acquir. Immune Defic. Syndr. Hum. Retrovirol,
doi:10.1097/00042560-199605010-00004Lerner, Wagaman, Phillips, Prospero-García, Henriksen et al., Increased mutation frequency of feline immunodeficiency virus lacking a functional deoxyuridine-triphosphatase, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.92.16.7480Li, Fedeles, Singh, Peng, Silvestre et al., Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2 -deoxycytidine, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.1405635111Li, Wang, Lavrijsen, Lamers, De Vries et al., SARS-CoV-2 omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination, Cell Res,
doi:10.1038/s41422-022-00618-wLoeb, Essigmann, Kazazi, Zhang, Rose et al., Lethal mutagenesis of HIV with mutagenic nucleoside analogs, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.96.4.1492Lutchman, Danehower, Song, Liang, Hoofnagle et al., Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy, Gastroenterology,
doi:10.1053/j.gastro.2007.03.035Ma, Frutos-Beltrán, Kang, Pannecouque, De Clercq et al., Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses, Chem. Soc. Rev,
doi:10.1039/D0CS01084GMangeat, Turelli, Caron, Friedli, Perrin et al., Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts, Nature,
doi:10.1038/nature01709Mansky, Bernard, 3 -Azido-3 -deoxythymidine (AZT) and AZT-resistant reverse transcriptase can increase the in vivo mutation rate of human immunodeficiency virus type 1, J. Virol,
doi:10.1128/JVI.74.20.9532-9539.2000Mansky, Le Rouzic, Benichou, Gajary, Influence of reverse transcriptase variants, drugs, and Vpr on human immunodeficiency virus type 1 mutant frequencies, J. Virol,
doi:10.1128/JVI.77.3.2071-2080.2003Mansky, The mutation rate of human immunodeficiency virus type 1 is influenced by the vpr gene, Virology,
doi:10.1006/viro.1996.0436Martín-Hernández, Domingo, Menéndez-Arias, Human immunodeficiency virus type 1 reverse transcriptase: Role of Tyr115 in deoxynucleotide binding and misinsertion fidelity of DNA synthesis, EMBO J,
doi:10.1002/j.1460-2075.1996.tb00816.xMcdaniel, Patterson, Mansky, Distinct dual antiviral mechanism that enhances hepatitis B virus mutagenesis and reduces viral DNA synthesis, Antiviral. Res,
doi:10.1016/j.antiviral.2019.104540Mejer, 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.01417-20Mejer, Galli, Ramirez, Fahnøe, Benfield et al., Ribavirin inhibition of cell-culture infectious hepatitis C genotype 1-3 viruses is strain-dependent, Virology,
doi:10.1016/j.virol.2019.09.014Menéndez-Arias, Molecular basis of fidelity of DNA synthesis and nucleotide specificity of retroviral reverse transcriptases, Prog. Nucleic Acid Res. Mol. Biol,
doi:10.1016/s0079-6603(02)71042-8Menéndez-Arias, Mutation rates and intrinsic fidelity of retroviral reverse transcriptases, CrossRef,
doi:10.3390/v1031137Moreno, Tejero, De La Torre, Domingo, Martín, Mutagenesis-mediated virus extinction: Virus-dependent effect of viral load on sensitivity to lethal defection, PLoS ONE,
doi:10.1371/journal.pone.0032550Mullins, Heath, Hughes, Kicha, Styrchak et al., Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461, PLoS ONE
Naydenova, Muir, Wu, Zhang, Coscia et al., Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.2021946118O'neil, Sun, Yu, Ron, Dougherty et al., Mutational analysis of HIV-1 long terminal repeats to explore the relative contribution of reverse transcriptase and RNA polymerase II to viral mutagenesis, J. Biol. Chem,
doi:10.1074/jbc.M204774200Ortega-Prieto, Sheldon, Grande-Pérez, Tejero, Gregori et al., Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis, PLoS ONE,
doi:10.1371/journal.pone.0071039Padhi, Dandapat, Saudagar, Uversky, Tripathi, Interface-based design of the favipiravir-binding site in SARS-CoV-2 RNA-dependent RNA polymerase reveals mutations conferring resistance to chain termination, FEBS Lett,
doi:10.1002/1873-3468.14182Paeshuyse, Dallmeier, Neyts, Ribavirin for the treatment of chronic hepatitis C virus infection: A review of the proposed mechanisms of action, Curr. Opin. Virol,
doi:10.1016/j.coviro.2011.10.030Painter, Natchus, Cohen, Holman, Painter, Developing a direct acting, orally available antiviral agent in a pandemic: The evolution of molnupiravir as a potential treatment for COVID-19, Curr. Opin. Virol,
doi:10.1016/j.coviro.2021.06.003Pauly, Lauring, Effective lethal mutagenesis of influenza virus by three nucleoside analogs, J. Virol
Perales, Domingo, Antiviral strategies based on lethal mutagenesis and error threshold, Curr. Top. Microbiol. Immunol,
doi:10.1007/82_2015_459Pfeiffer, Kirkegaard, A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.1232294100Qiu, Patterson, Bonnac, Geraghty, Nucleobases and corresponding nucleosides display potent antiviral activities against dengue virus possibly through viral lethal mutagenesis, PLoS Negl. Trop. Dis,
doi:10.1371/journal.pntd.0006421Ramírez-Olivencia, Estébanez, Membrillo, Ybarra, Uso de ribavirina en virus distintos de la hepatitis C. una revisión de la evidencia, Enferm. Infecc. Microbiol. Clin. (Engl,
doi:10.1016/j.eimc.2018.05.008Rawson, Daly, Xie, Clouser, Landman et al., 5-Azacytidine enhances the mutagenesis of HIV-1 by reduction to 5-aza-2 -deoxycytidine, Antimicrob. Agents Chemother,
doi:10.1128/AAC.03084-15Rawson, Heineman, Beach, Martin, Schnettler et al., 5,6-Dihydro-5-aza-2 -deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors, Bioorg. Med. Chem,
doi:10.1016/j.bmc.2013.08.023Rawson, Landman, Reilly, Bonnac, Patterson et al., Lack of mutational hot spots during decitabine-mediated HIV-1 mutagenesis, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01644-15Rawson, Roth, Xie, Daly, Clouser et al., Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase, Bioorg. Med. Chem,
doi:10.1016/j.bmc.2016.03.052Rosenke, Hansen, Schwarz, Feldmann, Haddock et al., Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model, Nat. Commun,
doi:10.1038/s41467-021-22580-8Roth, Mcdaniel, Daly, Talledge, Greggs et al., Distinct antiretroviral mechanisms elicited by a viral mutagen, J. Mol. Biol,
doi:10.1016/j.jmb.2021.167111Ruiz-Jarabo, Ly, Domingo, De La Torre, Lethal mutagenesis of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), Virology,
doi:10.1016/S0042-6822(02)00046-6Sangawa, Komeno, Nishikawa, Yoshida, Takahashi et al., Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase, Antimicrob. Agents Chemother,
doi:10.1128/AAC.00649-13Schultz, Johnson, Ayyanathan, Miller, Whig et al., Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2, Nature
Seier, Zilberberg, Zeiger, Lovett, Azidothymidine and other chain terminators are mutagenic for template-switchgenerated genetic mutations, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.1116160109Shah, Curr, Hamburgh, Parniak, Mitsuya et al., Differential influence of nucleoside analog-resistance mutations K65R and L74V on the overall mutation rate and error specificity of human immunodeficiency virus type 1 reverse transcriptase, J. Biol. Chem,
doi:10.1016/S0021-9258(19)61477-8Shannon, Selisko, Le, Huchting, Touret et al., Rapid incorporation of favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis, Nat. Commun,
doi:10.1038/s41467-020-18463-zSheahan, Sims, Zhou, Graham, Pruijssers et al., None
Sheehy, Gaddis, Choi, Malim, Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein, Nature,
doi:10.1038/nature00939Sidwell, Huffman, Khare Lois, Allen, Witkowski Roland et al., Broad-spectrum antiviral activity of virazole: 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, Science,
doi:10.1126/science.177.4050.705Sierra, Airaksinen, González-López, Agudo, Arias et al., Foot-and-mouth disease virus mutant with decreased sensitivity to ribavirin: Implications for error catastrophe, J. Virol,
doi:10.1128/JVI.01606-06Stevens, An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice, Sci. Transl. Med,
doi:10.1126/scitranslmed.abb5883Sánchez-Jiménez, Olivares, De Ávila Lucas, Toledano, Gutiérrez-Rivas et al., Mutagen-mediated enhancement of HIV-1 replication in persistently infected cells, Virology,
doi:10.1016/j.virol.2011.12.016Takaori-Kondo, Shindo, HIV-1 Vif: A guardian of the virus that opens up a new era in the research field of restriction factors, Front Microbiol,
doi:10.3389/fmicb.2013.00034Tapia, Fernàndez, Parera, Gómez-Mariano, Clotet et al., Combination of a mutagenic agent with a reverse transcriptase inhibitor results in systematic inhibition of HIV-1 infection, Virology,
doi:10.1016/j.virol.2005.05.008Todt, Walter, Brown, Steinmann, Mutagenic effects of ribavirin on hepatitis E virus-Viral extinction versus selection of fitness-enhancing mutations, Viruses,
doi:10.3390/v8100283Toots, Yoon, Cox, Hart, Sticher et al., Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia, Sci. Transl. Med,
doi:10.1126/scitranslmed.aax5866Urakova, Kuznetsova, Crossman, Sokratian, Guthrie et al., β-D-N 4 -hydroxycytidine is a potent anti-alphavirus compound that induces a high level of mutations in the viral genome, J. Virol,
doi:10.1128/JVI.01965-17Vangeel, Chiu, De Jonghe, Maes, Slechten et al., molnupiravir and nirmatrelvir remain active against SARS-CoV-2 omicron and other variants of concern, Antiviral. Res,
doi:10.1016/j.antiviral.2022.105252Vignuzzi, Stone, Andino, Ribavirin and lethal mutagenesis of poliovirus: Molecular mechanisms, resistance and biological implications, Virus Res,
doi:10.1016/j.virusres.2004.11.007Vivet-Boudou, Isel, El Safadi, Smyth, Laumond et al., Evaluation of anti-HIV-1 mutagenic nucleoside analogues, J. Biol. Chem,
doi:10.1074/jbc.M114.616383Wang, Li, Yuan, Gao, Lan et al., In vitro assessment of combinations of enterovirus inhibitors against enterovirus 71, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01073-16Waters, Warren, Hughes, Lewis, Zhang, Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: The special case of molnupiravir, Environ. Mol. Mutagen,
doi:10.1002/em.22471Young, Lindsay, Lee, Liu, He et al., Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy, Hepatology,
doi:10.1002/hep.1840380413Zhou, Hill, Sarkar, Tse, Woodburn et al., β-D-N 4 -hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells, J. Infect. Dis,
doi:10.1093/infdis/jiab247Zhou, Liu, Baroudy, Malcolm, Reyes, The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA, Virology,
doi:10.1016/S0042-6822(03)00152-1Álvarez, Sebastián-Martín, García-Marquina, Menéndez-Arias, Fidelity of classwide-resistant HIV-2 reverse transcriptase and differential contribution of K65R to the accuracy of HIV-1 and HIV-2 reverse transcriptases, Sci. Rep,
doi:10.1038/srep44834{ 'indexed': {'date-parts': [[2022, 4, 21]], 'date-time': '2022-04-21T21:49:24Z', 'timestamp': 1650577764252},
'reference-count': 152,
'publisher': 'MDPI AG',
'issue': '4',
'license': [ { 'start': { 'date-parts': [[2022, 4, 18]],
'date-time': '2022-04-18T00:00:00Z',
'timestamp': 1650240000000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'funder': [ { 'name': 'Ministerio de Ciencia e Innovación',
'award': ['PID2019-104176RB-I00/AEI/10.13039/501100011033']}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:p>In RNA viruses, a small increase in their mutation rates can be sufficient to exceed '
'their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use '
'of mutagens, driving viral populations to extinction. Extinction catastrophe can be '
'experimentally induced by promutagenic nucleosides in cell culture models. The loss of HIV '
'infectivity has been observed after passage in 5-hydroxydeoxycytidine or '
'5,6-dihydro-5-aza-2′-deoxycytidine while producing a two-fold increase in the viral mutation '
'frequency. Among approved nucleoside analogs, experiments with polioviruses and other RNA '
'viruses suggested that ribavirin can be mutagenic, although its mechanism of action is not '
'clear. Favipiravir and molnupiravir exert an antiviral effect through lethal mutagenesis. '
'Both drugs are broad-spectrum antiviral agents active against RNA viruses. Favipiravir '
'incorporates into viral RNA, affecting the G→A and C→U transition rates. Molnupiravir (a '
'prodrug of β-d-N4-hydroxycytidine) has been recently approved for the treatment of SARS-CoV-2 '
'infection. Its triphosphate derivative can be incorporated into viral RNA and extended by the '
'coronavirus RNA polymerase. Incorrect base pairing and inefficient extension by the '
'polymerase promote mutagenesis by increasing the G→A and C→U transition frequencies. Despite '
'having remarkable antiviral action and resilience to drug resistance, carcinogenic risks and '
'genotoxicity are important concerns limiting their extended use in antiviral '
'therapy.</jats:p>',
'DOI': '10.3390/v14040841',
'type': 'journal-article',
'created': {'date-parts': [[2022, 4, 20]], 'date-time': '2022-04-20T06:04:22Z', 'timestamp': 1650434662000},
'page': '841',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity',
'prefix': '10.3390',
'volume': '14',
'author': [ { 'ORCID': 'http://orcid.org/0000-0003-1992-7976',
'authenticated-orcid': False,
'given': 'Ikbel',
'family': 'Hadj Hassine',
'sequence': 'first',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-0145-7240',
'authenticated-orcid': False,
'given': 'Manel',
'family': 'Ben M’hadheb',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-1251-6640',
'authenticated-orcid': False,
'given': 'Luis',
'family': 'Menéndez-Arias',
'sequence': 'additional',
'affiliation': []}],
'member': '1968',
'published-online': {'date-parts': [[2022, 4, 18]]},
'reference': [ {'key': 'ref1', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.00694-10'},
{ 'key': 'ref2',
'doi-asserted-by': 'publisher',
'DOI': '10.1146/annurev-virology-091919-105900'},
{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.212514799'},
{ 'key': 'ref4',
'series-title': 'From Strange Simplicity to Complex Familiarity: A Treatise on Matter, '
'Information, Life and Thought',
'author': 'Eigen',
'year': '2013'},
{ 'key': 'ref5',
'doi-asserted-by': 'publisher',
'DOI': '10.1146/annurev.bi.42.070173.001511'},
{'key': 'ref6', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.54.4.1189'},
{'key': 'ref7', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.54.2.579'},
{'key': 'ref8', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/genetics/148.4.1667'},
{'key': 'ref9', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.96.24.13910'},
{'key': 'ref10', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/82_2015_459'},
{'key': 'ref11', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/jvi.64.8.3960-3962.1990'},
{ 'key': 'ref12',
'doi-asserted-by': 'publisher',
'DOI': '10.1146/annurev.micro.58.030603.123649'},
{'key': 'ref13', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.96.4.1492'},
{'key': 'ref14', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s00018-016-2299-6'},
{'key': 'ref15', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1003855'},
{'key': 'ref16', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01031-17'},
{'key': 'ref17', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.7824947'},
{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virusres.2016.12.019'},
{'key': 'ref19', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/v1031137'},
{'key': 'ref20', 'doi-asserted-by': 'publisher', 'DOI': '10.1074/jbc.M204774200'},
{'key': 'ref21', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/s0079-6603(02)71042-8'},
{'key': 'ref22', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/jvi.66.3.1791-1794.1992'},
{'key': 'ref23', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/jvi.68.4.2313-2319.1994'},
{'key': 'ref24', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.92.16.7480'},
{'key': 'ref25', 'doi-asserted-by': 'publisher', 'DOI': '10.1006/viro.1996.0436'},
{'key': 'ref26', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/nature00939'},
{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/nature01709'},
{'key': 'ref28', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fmicb.2013.00034'},
{'key': 'ref29', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0021-9258(19)61477-8'},
{'key': 'ref30', 'doi-asserted-by': 'publisher', 'DOI': '10.1042/BJ20101852'},
{ 'key': 'ref31',
'doi-asserted-by': 'publisher',
'DOI': '10.1002/j.1460-2075.1996.tb00816.x'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.1074/jbc.M910361199'},
{'key': 'ref33', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.77.3.2071-2080.2003'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virusres.2017.01.026'},
{'key': 'ref35', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virusres.2017.01.020'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.coviro.2021.03.010'},
{'key': 'ref37', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.molcel.2020.07.027'},
{'key': 'ref38', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0065-3527(06)66005-3'},
{'key': 'ref39', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01296-07'},
{'key': 'ref40', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1000896'},
{'key': 'ref41', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/jvi.66.5.3093-3100.1992'},
{'key': 'ref42', 'doi-asserted-by': 'publisher', 'DOI': '10.1097/00042560-199605010-00004'},
{'key': 'ref43', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/jvi.71.6.4254-4263.1997'},
{'key': 'ref44', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.74.20.9532-9539.2000'},
{'key': 'ref45', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01406-09'},
{'key': 'ref46', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jmb.2021.167111'},
{'key': 'ref47', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.03084-15'},
{'key': 'ref48', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virol.2011.12.016'},
{'key': 'ref49', 'doi-asserted-by': 'publisher', 'DOI': '10.1074/jbc.M114.616383'},
{'key': 'ref50', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.01644-15'},
{'key': 'ref51', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0165-6147(02)02054-0'},
{'key': 'ref52', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.tips.2021.10.004'},
{'key': 'ref53', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virol.2005.05.008'},
{'key': 'ref54', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.1116160109'},
{'key': 'ref55', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2005.03.004'},
{'key': 'ref56', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.1405635111'},
{'key': 'ref57', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0015135'},
{'key': 'ref58', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0014-5793(97)01572-X'},
{'key': 'ref59', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bmc.2013.08.023'},
{'key': 'ref60', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.semcdb.2014.03.030'},
{'key': 'ref61', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/genes12071096'},
{'key': 'ref62', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01006-10'},
{'key': 'ref63', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bmc.2016.03.052'},
{'key': 'ref64', 'doi-asserted-by': 'publisher', 'DOI': '10.1099/vir.0.069864-0'},
{'key': 'ref65', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/srep44834'},
{'key': 'ref66', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2019.104540'},
{'key': 'ref67', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.7041255'},
{'key': 'ref68', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/infdis/jiab247'},
{'key': 'ref69', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/82191'},
{'key': 'ref70', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/jm060872x'},
{'key': 'ref71', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01028-07'},
{'key': 'ref72', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.01056-07'},
{'key': 'ref73', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.05712-11'},
{'key': 'ref74', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0032550'},
{'key': 'ref75', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0042-6822(03)00144-2'},
{'key': 'ref76', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.77.12.7131-7138.2003'},
{'key': 'ref77', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01606-06'},
{'key': 'ref78', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1001072'},
{'key': 'ref79', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virusres.2017.03.014'},
{'key': 'ref80', 'doi-asserted-by': 'publisher', 'DOI': '10.7554/eLife.03679'},
{'key': 'ref81', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pntd.0006421'},
{'key': 'ref82', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.00380-18'},
{'key': 'ref83', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2005.04.002'},
{'key': 'ref84', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.01400-17'},
{'key': 'ref85', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.75.17.8074-8081.2001'},
{'key': 'ref86', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.76.17.8505-8517.2002'},
{'key': 'ref87', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0042-6822(03)00152-1'},
{'key': 'ref88', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.00201-09'},
{'key': 'ref89', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0071039'},
{'key': 'ref90', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.02778-12'},
{'key': 'ref91', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.01653-19'},
{'key': 'ref92', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0164691'},
{'key': 'ref93', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/v8100283'},
{'key': 'ref94', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01965-17'},
{'key': 'ref95', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-020-18463-z'},
{'key': 'ref96', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.01348-19'},
{'key': 'ref97', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-018-19829-6'},
{'key': 'ref98', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.03483-14'},
{'key': 'ref99', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/scitranslmed.aax5866'},
{'key': 'ref100', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.0408871102'},
{'key': 'ref101', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.77.1.481-488.2003'},
{'key': 'ref102', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.00874-07'},
{'key': 'ref103', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.00669-19'},
{'key': 'ref104', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0042-6822(02)00046-6'},
{'key': 'ref105', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2019.06.001'},
{'key': 'ref106', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virusres.2004.11.007'},
{'key': 'ref107', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.eimc.2018.05.008'},
{'key': 'ref108', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/rmv.483'},
{'key': 'ref109', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.coviro.2011.10.030'},
{'key': 'ref110', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.0406927102'},
{'key': 'ref111', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.177.4050.705'},
{'key': 'ref112', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/v13040667'},
{'key': 'ref113', 'doi-asserted-by': 'publisher', 'DOI': '10.1074/jbc.274.5.2706'},
{'key': 'ref114', 'doi-asserted-by': 'publisher', 'DOI': '10.1074/jbc.M002671200'},
{'key': 'ref115', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.1232294100'},
{'key': 'ref116', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.02420-09'},
{'key': 'ref117', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/hep.1840380413'},
{'key': 'ref118', 'doi-asserted-by': 'publisher', 'DOI': '10.1053/j.gastro.2007.03.035'},
{'key': 'ref119', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virol.2019.09.014'},
{'key': 'ref120', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.01417-20'},
{'key': 'ref121', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.1007626107'},
{'key': 'ref122', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virol.2018.07.030'},
{'key': 'ref123', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2018.03.003'},
{'key': 'ref124', 'doi-asserted-by': 'publisher', 'DOI': '10.1177/2040206618764483'},
{'key': 'ref125', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.00649-13'},
{'key': 'ref126', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0068347'},
{'key': 'ref127', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.02346-12'},
{'key': 'ref128', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.1811345115'},
{'key': 'ref129', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.ppat.1008937'},
{'key': 'ref130', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/jac/dku209'},
{'key': 'ref131', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.01073-16'},
{'key': 'ref132', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.2021946118'},
{'key': 'ref133', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/1873-3468.14182'},
{'key': 'ref134', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2021.105078'},
{'key': 'ref135', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/scitranslmed.abb5883'},
{'key': 'ref136', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jbc.2021.100770'},
{'key': 'ref137', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41594-021-00651-0'},
{'key': 'ref138', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0CP05297C'},
{'key': 'ref139', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-021-22580-8'},
{'key': 'ref140', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41564-020-00835-2'},
{'key': 'ref141', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2116044'},
{'key': 'ref142', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/scitranslmed.abl7430'},
{'key': 'ref143', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/infdis/jiab361'},
{'key': 'ref144', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41422-022-00618-w'},
{'key': 'ref145', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2022.105252'},
{'key': 'ref146', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jbc.2021.100867'},
{'key': 'ref147', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ebiom.2021.103595'},
{'key': 'ref148', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-022-04482-x'},
{'key': 'ref149', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.coviro.2021.06.003'},
{'key': 'ref150', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/em.22373'},
{'key': 'ref151', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/em.22471'},
{'key': 'ref152', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0CS01084G'}],
'container-title': 'Viruses',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/1999-4915/14/4/841/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 4, 20]],
'date-time': '2022-04-20T06:12:44Z',
'timestamp': 1650435164000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/1999-4915/14/4/841'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 4, 18]]},
'references-count': 152,
'journal-issue': {'issue': '4', 'published-online': {'date-parts': [[2022, 4]]}},
'alternative-id': ['v14040841'],
'URL': 'http://dx.doi.org/10.3390/v14040841',
'relation': {},
'ISSN': ['1999-4915'],
'subject': ['Virology', 'Infectious Diseases'],
'container-title-short': 'Viruses',
'published': {'date-parts': [[2022, 4, 18]]}}
