Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting

Fran Robson, Khadija Shahed Khan, Thi Khanh Le, Clément Paris, Sinem Demirbag, Peter Barfuss, Palma Rocchi, Wai-Lung Ng, Fran Robson, Khadija Shahed Khan, Thi Khanh Le, Clément Paris, Sinem Demirbag, Peter Barfuss, Palma Rocchi, Wai-Lung Ng

Abstract

The coronavirus disease 2019 (COVID-19) that is wreaking havoc on worldwide public health and economies has heightened awareness about the lack of effective antiviral treatments for human coronaviruses (CoVs). Many current antivirals, notably nucleoside analogs (NAs), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription. Here, we review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. We also consider existing nucleoside analogs and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism.

Keywords: ASO; CoV; ExoN; NA; anti-coronavirus drugs; antisense oligonucleotide; coronavirus; exonuclease; non-structural protein 14; nsp14; nucleoside analog.

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Single-Stranded RNA Genome of SARS-CoV-2 Two-thirds of the genome encodes two large polyproteins, pp1a and pp1ab, that are cleaved into 16 non-structural proteins. The last one-third of the genome encodes structural and accessory proteins. This figure was created with BioRender.
Figure 2
Figure 2
Virus Replication Mechanism To enter in the host cell, first the virus binds to the ACE2 receptor (1) to initiate the viral entry (2), the vacuole containing the virus is then internalized (3) and the membrane fuses with the virus (4) in order to release it (5) into the cytoplasm of host cell. The genome is then translated to produce the polyproteins pp1a and pp1ab (6), which are cleaved by proteases (7) to yield the 16 NSPs that form the RNA replicase-transcriptase complex (8). Viral genome is duplicated and mRNA encoding structural proteins are transcribed (9). Then, the subgenomic mRNAs are translated into structural proteins (10). The formation of the new virion takes place on modified intracellular membranes that are derived from the rough endoplasmic reticulum (ER) in the perinuclear region (11). The new virion is then released (12). In red are localized the sites of action of a number of small-molecule antivirals. This figure was created with BioRender.
Figure 3
Figure 3
Model of the Core Replication and Proofreading Complex of SARS-CoV Nsp12-RdRp replicates and transcribes the genome and sgmRNAs. Nsp7/nsp8 proteins confer processivity to the polymerase. Nsp13 unwinds dsRNA ahead of the polymerase. Nsp14-ExoN complexed with its co-factor nsp10 proofreads the nascent RNA strand and excises misincorporated nucleotides. Nsp13, an unknown GTPase, Nsp14-N7-methyltransferase, and the Nsp16-2′-O-methyltransferase/Nsp10 complex are involved in the capping mechanism. This figure was created with BioRender.
Figure 4
Figure 4
The Overall Structure of Nonstructural Protein 14 (A) Cartoon representation of the structure of the nsp14. The N-terminal exonuclease domain (aquamarine) and C-terminal N7-methyltransferase (light magenta) are connected by a flexible interdomain loop (black). The amino acid residues that coordinate zinc fingers (ZF) (slate blue) and magnesium cofactor (Mg2+) (pea green) are shown as sticks. Protein structure is retrieved from Protein Data Bank (PDB ID: 5C8U; Ma et al., 2015). (B) Detailed cartoon representation of the catalytic DEEDh residues. DEEDh domain comprises Asp90, Glu92, Glu191, Asp273, and His268 amino acids residues that are located in the exonuclease domain (aquamarine) of the nsp14. Mg2+ cofactor (pea green) is coordinated by Asp90 and Glu191 and is thought to facilitate the removal of misincorporated nucleotides. The second Mg2+ is shown tentatively; isothermal titration calorimetry predicted a two-metal binding mode for divalent cations, but crystallography data showed only one (Chen et al., 2007). The protein structure was retrieved from Protein Data Bank (PDB: 5C8U; Ma et al., 2015).
Figure 5
Figure 5
ASO Technology in Therapy against SARS-CoV-2 Antisense oligonucleotides (ASOs) are conjugated with a carrier that allows delivery into the cells (1). Lipid-modified ASOs (LASO) self-assemble into nanomicelles (2) and encapsulate an antiviral molecule such as an NA (3). These nanomicelles are able to enter the cell without any transfection agents (4). Once inside the cell, ASO, LASO, and the encapsulated drugs are released (5). ASOs are administered via cationic polymers and are released through the proton sponge effect (the presence of the weakly basic molecule causes the endosome to burst). LASOs enter via the macropinocytosis mechanism and are released through interaction with the endosomal membrane. The intracellular ASOs/LASOs match to their complementary sequences (6), leading either to genome degradation (through RNaseH activity) or replication/transcription/translation blocks due to steric block formation. The NAs can interfere with the RNA replication and transcription by targeting RdRp as described above (7). This figure was created with BioRender.

References

    1. Abbott T.R., Dhamdhere G., Liu Y., Lin X., Goudy L., Zeng L., Chemparathy A., Chmura S., Heaton N.S., Debs R., et al. Development of CRISPR as an Antiviral Strategy to Combat SARS-CoV-2 and Influenza. Cell. 2020;181:865–876.
    1. Adedeji A.O., Marchand B., Te Velthuis A.J.W., Snijder E.J., Weiss S., Eoff R.L., Singh K., Sarafianos S.G. Mechanism of nucleic acid unwinding by SARS-CoV helicase. PLoS ONE. 2012;7:e36521.
    1. Agostini M.L., Andres E.L., Sims A.C., Graham R.L., Sheahan T.P., Lu X., Smith E.C., Case J.B., Feng J.Y., Jordan R., et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio. 2018;9 doi: 10.1128/mBio.00221-18. Published online March 6, 2018.
    1. Agostini M.L., Pruijssers A.J., Chappell J.D., Gribble J., Lu X., Andres E.L., Bluemling G.R., Lockwood M.A., Sheahan T.P., Sims A.C., et al. Small-Molecule Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. J. Virol. 2019;93 doi: 10.1128/JVI.01348-19. Published online November 26, 2019.
    1. Almeida J.D., Berry D.M., Cunningham C.H., Hamre D., Hofstad M.S., Mallucci L., McIntosh K., Tyrrell D.A.J. Virology: Coronaviruses. Nature. 1968;220:650. 650.
    1. Angelini M.M., Akhlaghpour M., Neuman B.W., Buchmeier M.J. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. MBio. 2013;4 doi: 10.1128/mBio.00524-13. Published online August 13, 2013.
    1. Appleby T.C., Perry J.K., Murakami E., Barauskas O., Feng J., Cho A., Fox D., 3rd, Wetmore D.R., McGrath M.E., Ray A.S., et al. Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase. Science. 2015;347:771–775.
    1. Baranovich T., Wong S.-S., Armstrong J., Marjuki H., Webby R.J., Webster R.G., Govorkova E.A. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J. Virol. 2013;87:3741–3751.
    1. Barnard D.L., Hubbard V.D., Burton J., Smee D.F., Morrey J.D., Otto M.J., Sidwell R.W. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine. Antivir. Chem. Chemother. 2004;15:15–22.
    1. Becares M., Pascual-Iglesias A., Nogales A., Sola I., Enjuanes L., Zuñiga S. Mutagenesis of Coronavirus nsp14 Reveals Its Potential Role in Modulation of the Innate Immune Response. J. Virol. 2016;90:5399–5414.
    1. Beese L.S., Steitz T.A. Structural basis for the 3′-5′ exonuclease activity of Escherichia coli DNA polymerase I: a two metal ion mechanism. EMBO J. 1991;10:25–33.
    1. Bhardwaj K., Guarino L., Kao C.C. The severe acute respiratory syndrome coronavirus Nsp15 protein is an endoribonuclease that prefers manganese as a cofactor. J. Virol. 2004;78:12218–12224.
    1. Bosch B.J., van der Zee R., de Haan C.A.M., Rottier P.J.M. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J. Virol. 2003;77:8801–8811.
    1. Bouvet M., Debarnot C., Imbert I., Selisko B., Snijder E.J., Canard B., Decroly E. In vitro reconstitution of SARS-coronavirus mRNA cap methylation. PLoS Pathog. 2010;6:e1000863.
    1. Bouvet M., Imbert I., Subissi L., Gluais L., Canard B., Decroly E. RNA 3′-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proc. Natl. Acad. Sci. USA. 2012;109:9372–9377.
    1. Bouvet M., Lugari A., Posthuma C.C., Zevenhoven J.C., Bernard S., Betzi S., Imbert I., Canard B., Guillemot J.-C., Lécine P., et al. Coronavirus Nsp10, a critical co-factor for activation of multiple replicative enzymes. J. Biol. Chem. 2014;289:25783–25796.
    1. Case J.B., Ashbrook A.W., Dermody T.S., Denison M.R. Mutagenesis of S-Adenosyl-l-Methionine-Binding Residues in Coronavirus nsp14 N7-Methyltransferase Demonstrates Differing Requirements for Genome Translation and Resistance to Innate Immunity. J. Virol. 2016;90:7248–7256.
    1. Chan J.F.W., Lau S.K.P., To K.K.W., Cheng V.C.C., Woo P.C.Y., Yuen K.-Y. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin. Microbiol. Rev. 2015;28:465–522.
    1. Chen Y., Guo D. Molecular mechanisms of coronavirus RNA capping and methylation. Virol. Sin. 2016;31:3–11.
    1. Chen P., Jiang M., Hu T., Liu Q., Chen X.S., Guo D. Biochemical characterization of exoribonuclease encoded by SARS coronavirus. J. Biochem. Mol. Biol. 2007;40:649–655.
    1. Chen Y., Cai H., Pan J., Xiang N., Tien P., Ahola T., Guo D. Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc. Natl. Acad. Sci. USA. 2009;106:3484–3489.
    1. Chien M., Anderson T.K., Jockusch S., Tao C., Kumar S., Li X., Russo J.J., Kirchdoerfer R.N., Ju J. Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase. bioRxiv. 2020 doi: 10.1101/2020.03.18.997585.
    1. Compton S.R., Barthold S.W., Smith A.L. The cellular and molecular pathogenesis of coronaviruses. Lab. Anim. Sci. 1993;43:15–28.
    1. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020;5:536–544.
    1. Cottam E.M., Maier H.J., Manifava M., Vaux L.C., Chandra-Schoenfelder P., Gerner W., Britton P., Ktistakis N.T., Wileman T. Coronavirus nsp6 proteins generate autophagosomes from the endoplasmic reticulum via an omegasome intermediate. Autophagy. 2011;7:1335–1347.
    1. Crosby J.R., Zhao C., Jiang C., Bai D., Katz M., Greenlee S., Kawabe H., McCaleb M., Rotin D., Guo S., Monia B.P. Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice. J. Cyst. Fibros. 2017;16:671–680.
    1. Cui J., Li F., Shi Z.-L. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol. 2019;17:181–192.
    1. De Clercq E., Neyts J. In: Antiviral Strategies. Kräusslich H.-G., Bartenschlager R., editors. Springer Berlin Heidelberg; 2009. Antiviral Agents Acting as DNA or RNA Chain Terminators; pp. 53–84.
    1. de Vries A.A.F., Horzinek M.C., Rottier P.J.M., de Groot R.J. The Genome Organization of the Nidovirales: Similarities and Differences between Arteri-, Toro-, and Coronaviruses. Semin. Virol. 1997;8:33–47.
    1. de Wit E., Feldmann F., Cronin J., Jordan R., Okumura A., Thomas T., Scott D., Cihlar T., Feldmann H. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc. Natl. Acad. Sci. USA. 2020;117:6771–6776.
    1. Decroly E., Imbert I., Coutard B., Bouvet M., Selisko B., Alvarez K., Gorbalenya A.E., Snijder E.J., Canard B. Coronavirus nonstructural protein 16 is a cap-0 binding enzyme possessing (nucleoside-2'O)-methyltransferase activity. J. Virol. 2008;82:8071–8084.
    1. Decroly E., Ferron F., Lescar J., Canard B. Conventional and unconventional mechanisms for capping viral mRNA. Nat. Rev. Microbiol. 2011;10:51–65.
    1. Denison M.R., Graham R.L., Donaldson E.F., Eckerle L.D., Baric R.S. Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol. 2011;8:270–279.
    1. Deval J. Antimicrobial strategies: inhibition of viral polymerases by 3′-hydroxyl nucleosides. Drugs. 2009;69:151–166.
    1. Diab R., Degobert G., Hamoudeh M., Dumontet C., Fessi H. Nucleoside analogue delivery systems in cancer therapy. Expert Opin. Drug Deliv. 2007;4:513–531.
    1. Dos Ramos F., Carrasco M., Doyle T., Brierley I. Programmed -1 ribosomal frameshifting in the SARS coronavirus. Biochem. Soc. Trans. 2004;32:1081–1083.
    1. Driouich J.-S., Cochin M., Lingas G., Moureau G., Touret F., Petit P.R., Piorkowski G., Barthélémy K., Coutard B., Guedj J., et al. Favipiravir and severe acute respiratory syndrome coronavirus 2 in hamster model. bioRxiv. 2020 doi: 10.1101/2020.07.07.191775.
    1. Duan M., Zhou Z., Lin R.-X., Yang J., Xia X.-Z., Wang S.-Q. In vitro and in vivo protection against the highly pathogenic H5N1 influenza virus by an antisense phosphorothioate oligonucleotide. Antivir. Ther. (Lond.) 2008;13:109–114.
    1. Eckerle L.D., Lu X., Sperry S.M., Choi L., Denison M.R. High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J. Virol. 2007;81:12135–12144.
    1. Eckerle L.D., Becker M.M., Halpin R.A., Li K., Venter E., Lu X., Scherbakova S., Graham R.L., Baric R.S., Stockwell T.B., et al. Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog. 2010;6:e1000896.
    1. Egloff M.-P., Ferron F., Campanacci V., Longhi S., Rancurel C., Dutartre H., Snijder E.J., Gorbalenya A.E., Cambillau C., Canard B. The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world. Proc. Natl. Acad. Sci. USA. 2004;101:3792–3796.
    1. Elfiky A.A. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020;253:117592.
    1. Estola T. Coronaviruses, a new group of animal RNA viruses. Avian Dis. 1970;14:330–336.
    1. Feng J.Y. Addressing the selectivity and toxicity of antiviral nucleosides. Antivir. Chem. Chemother. 2018;26 2040206618758524.
    1. Ferron F., Subissi L., Silveira De Morais A.T., Le N.T.T., Sevajol M., Gluais L., Decroly E., Vonrhein C., Bricogne G., Canard B., Imbert I. Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proc. Natl. Acad. Sci. USA. 2018;115:E162–E171.
    1. Fung A., Jin Z., Dyatkina N., Wang G., Beigelman L., Deval J. Efficiency of incorporation and chain termination determines the inhibition potency of 2′-modified nucleotide analogs against hepatitis C virus polymerase. Antimicrob. Agents Chemother. 2014;58:3636–3645.
    1. Furuta Y., Takahashi K., Fukuda Y., Kuno M., Kamiyama T., Kozaki K., Nomura N., Egawa H., Minami S., Watanabe Y., et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Chemother. 2002;46:977–981.
    1. Furuta Y., Gowen B.B., Takahashi K., Shiraki K., Smee D.F., Barnard D.L. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100:446–454.
    1. Furuta Y., Komeno T., Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2017;93:449–463.
    1. Gabriel G., Nordmann A., Stein D.A., Iversen P.L., Klenk H.-D. Morpholino oligomers targeting the PB1 and NP genes enhance the survival of mice infected with highly pathogenic influenza A H7N7 virus. J. Gen. Virol. 2008;89:939–948.
    1. Gao Y., Yan L., Huang Y., Liu F., Zhao Y., Cao L., Wang T., Sun Q., Ming Z., Zhang L., et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020;368:779–782.
    1. Gorbalenya A.E., Enjuanes L., Ziebuhr J., Snijder E.J. Nidovirales: evolving the largest RNA virus genome. Virus Res. 2006;117:17–37.
    1. Gordon C.J., Tchesnokov E.P., Woolner E., Perry J.K., Feng J.Y., Porter D.P., Götte M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J. Biol. Chem. 2020;295:6785–6797.
    1. Gribble J., Pruijssers A.J., Agostini M.L., Anderson-Daniels J., Chappell J.D., Lu X., Stevens L.J., Routh A.L., Denison M.R. The coronavirus proofreading exoribonuclease mediates extensive viral recombination. bioRxiv. 2020 doi: 10.1101/2020.04.23.057786.
    1. Hillen H.S., Kokic G., Farnung L., Dienemann C. Structure of replicating SARS-CoV-2 polymerase. bioRxiv. 2020 doi: 10.1101/2020.04.27.063180.
    1. Huang C., Lokugamage K.G., Rozovics J.M., Narayanan K., Semler B.L., Makino S. SARS coronavirus nsp1 protein induces template-dependent endonucleolytic cleavage of mRNAs: viral mRNAs are resistant to nsp1-induced RNA cleavage. PLoS Pathog. 2011;7:e1002433.
    1. Hui D.S.C., Zumla A. Severe Acute Respiratory Syndrome: Historical, Epidemiologic, and Clinical Features. Infect. Dis. Clin. North Am. 2019;33:869–889.
    1. Hung I.F.-N., Lung K.-C., Tso E.Y.-K., Liu R., Chung T.W.-H., Chu M.-Y., Ng Y.-Y., Lo J., Chan J., Tam A.R., et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395:1695–1704.
    1. Imbert I., Guillemot J.-C., Bourhis J.-M., Bussetta C., Coutard B., Egloff M.-P., Ferron F., Gorbalenya A.E., Canard B. A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 2006;25:4933–4942.
    1. Jácome R., Campillo-Balderas J.A., Ponce de León S., Becerra A., Lazcano A. Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic. Sci. Rep. 2020;10:9294.
    1. Jin Z., Smith L.K., Rajwanshi V.K., Kim B., Deval J. The ambiguous base-pairing and high substrate efficiency of T-705 (Favipiravir) Ribofuranosyl 5′-triphosphate towards influenza A virus polymerase. PLoS ONE. 2013;8:e68347.
    1. Jordan P.C., Stevens S.K., Deval J. Nucleosides for the treatment of respiratory RNA virus infections. Antivir. Chem. Chemother. 2018;26 2040206618764483.
    1. Jordheim L.P., Durantel D., Zoulim F., Dumontet C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat. Rev. Drug Discov. 2013;12:447–464.
    1. Kahn J.S., McIntosh K. History and recent advances in coronavirus discovery. Pediatr. Infect. Dis. J. 2005;24(11, Suppl):S223–S227. discussion S226.
    1. Karaki S., Benizri S., Mejías R., Baylot V., Branger N., Nguyen T., Vialet B., Oumzil K., Barthélémy P., Rocchi P. Lipid-oligonucleotide conjugates improve cellular uptake and efficiency of TCTP-antisense in castration-resistant prostate cancer. J. Control. Release. 2017;258:1–9.
    1. Karaki S., Branger N., Benizri S., Barthélémy P., Rocchi P. WO2019175163A1; 2018. Evaluation de l’autonanovectorisation de l’oligonucléotide anti-TCTP comme stratégie innovante pour le traitement des cancers de prostate résistants à la castration [Patent]
    1. Karaki S., Paris C., Rocchi P. In: Antisense Therapy. Sharad S., Kapur S., editors. IntechOpen; 2019. Antisense Oligonucleotides, A Novel Developing Targeting Therapy.
    1. Kim D., Lee J.-Y., Yang J.-S., Kim J.W., Kim V.N., Chang H. The Architecture of SARS-CoV-2 Transcriptome. Cell. 2020;181:914–921.
    1. King A., Adams M., Carstens E., Lefkowitz E. Elsevier; 2012. Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses.
    1. Kumar P., Kumar B., Rajput R., Saxena L., Banerjea A.C., Khanna M. Cross-protective effect of antisense oligonucleotide developed against the common 3′ NCR of influenza A virus genome. Mol. Biotechnol. 2013;55:203–211.
    1. Lai M.M.C., Stohlman S.A. Comparative analysis of RNA genomes of mouse hepatitis viruses. J. Virol. 1981;38:661–670.
    1. Lai C.-C., Shih T.-P., Ko W.-C., Tang H.-J., Hsueh P.-R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int. J. Antimicrob. Agents. 2020;55:105924.
    1. Li G., De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV) Nat. Rev. Drug Discov. 2020;19:149–150.
    1. Liu H., Wang X., Wan G., Yang Z., Zeng H. Telbivudine versus entecavir for nucleos(t)ide-naive HBeAg-positive chronic hepatitis B: a meta-analysis. Am. J. Med. Sci. 2014;347:131–138.
    1. Liu S., Lien C.Z., Selvaraj P., Wang T.T. Evaluation of 19 antiviral drugs against SARS-CoV-2 Infection. bioRxiv. 2020 doi: 10.1101/2020.04.29.067983.
    1. Lo H.S., Hui K.P.Y., Lai H.-M., Khan K.S., Kaur S., Li Z., Chan A.K.N., Cheung H.H.-Y., Ng K.C., Ho J.C.W., et al. Simeprevir suppresses SARS-CoV-2 replication and synergizes with remdesivir. bioRxiv. 2020 doi: 10.1101/2020.05.26.116020.
    1. Luk H.K.H., Li X., Fung J., Lau S.K.P., Woo P.C.Y. Molecular epidemiology, evolution and phylogeny of SARS coronavirus. Infect. Genet. Evol. 2019;71:21–30.
    1. Ma Y., Wu L., Shaw N., Gao Y., Wang J., Sun Y., Lou Z., Yan L., Zhang R., Rao Z. Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex. Proc. Natl. Acad. Sci. USA. 2015;112:9436–9441.
    1. Malik Y.A. Properties of Coronavirus and SARS-CoV-2. Malays. J. Pathol. 2020;42:3–11.
    1. McGuigan C., Cahard D., Sheeka H.M., De Clercq E., Balzarini J. Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. J. Med. Chem. 1996;39:1748–1753.
    1. Mehellou Y., Rattan H.S., Balzarini J. The ProTide Prodrug Technology: From the Concept to the Clinic. J. Med. Chem. 2018;61:2211–2226.
    1. Minskaia E., Hertzig T., Gorbalenya A.E., Campanacci V., Cambillau C., Canard B., Ziebuhr J. Discovery of an RNA virus 3′->5′ exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc. Natl. Acad. Sci. USA. 2006;103:5108–5113.
    1. Naesens L., Guddat L.W., Keough D.T., van Kuilenburg A.B.P., Meijer J., Vande Voorde J., Balzarini J. Role of human hypoxanthine guanine phosphoribosyltransferase in activation of the antiviral agent T-705 (favipiravir) Mol. Pharmacol. 2013;84:615–629.
    1. Nan Y., Zhang Y.-J. Antisense Phosphorodiamidate Morpholino Oligomers as Novel Antiviral Compounds. Front. Microbiol. 2018;9:750.
    1. Narayanan K., Ramirez S.I., Lokugamage K.G., Makino S. Coronavirus nonstructural protein 1: Common and distinct functions in the regulation of host and viral gene expression. Virus Res. 2015;202:89–100.
    1. Neuman B.W., Stein D.A., Kroeker A.D., Paulino A.D., Moulton H.M., Iversen P.L., Buchmeier M.J. Antisense morpholino-oligomers directed against the 5′ end of the genome inhibit coronavirus proliferation and growth. J. Virol. 2004;78:5891–5899.
    1. Neuman B.W., Stein D.A., Kroeker A.D., Churchill M.J., Kim A.M., Kuhn P., Dawson P., Moulton H.M., Bestwick R.K., Iversen P.L., Buchmeier M.J. Inhibition, escape, and attenuated growth of severe acute respiratory syndrome coronavirus treated with antisense morpholino oligomers. J. Virol. 2005;79:9665–9676.
    1. Nguyen T.M., Zhang Y., Pandolfi P.P. Virus against virus: a potential treatment for 2019-nCov (SARS-CoV-2) and other RNA viruses. Cell Res. 2020;30:189–190.
    1. Noell B.C., Besur S.V., deLemos A.S. Changing the face of hepatitis C management - the design and development of sofosbuvir. Drug Des. Devel. Ther. 2015;9:2367–2374.
    1. Ogando N.S., Ferron F., Decroly E., Canard B., Posthuma C.C., Snijder E.J. The Curious Case of the Nidovirus Exoribonuclease: Its Role in RNA Synthesis and Replication Fidelity. Front. Microbiol. 2019;10:1813.
    1. Ogando N.S., Zevenhoven-Dobbe J.C., Posthuma C.C., Snijder E.J. The enzymatic activity of the nsp14 exoribonuclease is critical for replication of Middle East respiratory syndrome-coronavirus. bioRxiv. 2020 doi: 10.1101/2020.06.19.162529.
    1. Pan J., Peng X., Gao Y., Li Z., Lu X., Chen Y., Ishaq M., Liu D., Dediego M.L., Enjuanes L., Guo D. Genome-wide analysis of protein-protein interactions and involvement of viral proteins in SARS-CoV replication. PLoS ONE. 2008;3:e3299.
    1. Pedersen N.C., Perron M., Bannasch M., Montgomery E., Murakami E., Liepnieks M., Liu H. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J. Feline Med. Surg. 2019;21:271–281.
    1. Peng Y.-H., Lin C.-H., Lin C.-N., Lo C.-Y., Tsai T.-L., Wu H.-Y. Characterization of the Role of Hexamer AGUAAA and Poly(A) Tail in Coronavirus Polyadenylation. PLoS ONE. 2016;11:e0165077.
    1. Perales C., Domingo E. Antiviral strategies based on lethal mutagenesis and error threshold. Curr. Top. Microbiol. Immunol. 2016;392:323–339.
    1. Pruijssers A.J., Denison M.R. Nucleoside analogues for the treatment of coronavirus infections. Curr. Opin. Virol. 2019;35:57–62.
    1. Pyrc K., Bosch B.J., Berkhout B., Jebbink M.F., Dijkman R., Rottier P., van der Hoek L. Inhibition of human coronavirus NL63 infection at early stages of the replication cycle. Antimicrob. Agents Chemother. 2006;50:2000–2008.
    1. Rocchi P., Gissot A., Oumzil K., Acunzo J., Barthélémy P. WO2014195432; 2013. Hydrophobically modified antisense oligonucleotides comprising a triple alkyl chain [Patent]
    1. Rocchi P., Oumzil K., Acunzo J., Barthélémy P. WO2014195430; 2013. Hydrophobically modified antisense oligonucleotides comprising a cetal group [Patent]
    1. Saberi A., Gulyaeva A.A., Brubacher J.L., Newmark P.A., Gorbalenya A.E. A planarian nidovirus expands the limits of RNA genome size. PLoS Pathog. 2018;14:e1007314.
    1. Sangawa H., Komeno T., Nishikawa H., Yoshida A., Takahashi K., Nomura N., Furuta Y. Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob. Agents Chemother. 2013;57:5202–5208.
    1. Sawicki S.G., Sawicki D.L. In: Corona- and Related Viruses: Current Concepts in Molecular Biology and Pathogenesis, P.J. Talbot, and G.A. Levy. Boston M.A., editor. 1995. Coronaviruses use Discontinuous Extension for Synthesis of Subgenome-Length Negative Strands; pp. 499–506. Springer.
    1. Seley-Radtke K.L., Yates M.K. The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold. Antiviral Res. 2018;154:66–86.
    1. Sethna P.B., Hung S.L., Brian D.A. Coronavirus subgenomic minus-strand RNAs and the potential for mRNA replicons. Proc. Natl. Acad. Sci. USA. 1989;86:5626–5630.
    1. Sevajol M., Subissi L., Decroly E., Canard B., Imbert I. Insights into RNA synthesis, capping, and proofreading mechanisms of SARS-coronavirus. Virus Res. 2014;194:90–99.
    1. Seybert A., Hegyi A., Siddell S.G., Ziebuhr J. The human coronavirus 229E superfamily 1 helicase has RNA and DNA duplex-unwinding activities with 5′-to-3′ polarity. RNA. 2000;6:1056–1068.
    1. Shannon A., Le N.T., Selisko B., Eydoux C., Alvarez K., Guillemot J.-C., Decroly E., Peersen O., Ferron F., Canard B. Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites. Antiviral Res. 2020;178:104793.
    1. Shannon A., Selisko B., Le N.T.T., Huchting J., Touret F., Piorkowski G., Fattorini V., Ferron F., Decroly E., Meier C., et al. Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase. bioRxiv. 2020 doi: 10.1101/2020.05.15.098731.
    1. Sheahan T.P., Sims A.C., Graham R.L., Menachery V.D., Gralinski L.E., Case J.B., Leist S.R., Pyrc K., Feng J.Y., Trantcheva I., et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 2017;9:eaal3653.
    1. Sheahan T.P., Sims A.C., Leist S.R., Schäfer A., Won J., Brown A.J., Montgomery S.A., Hogg A., Babusis D., Clarke M.O., et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 2020;11:222.
    1. Sheahan T.P., Sims A.C., Zhou S., Graham R.L., Pruijssers A.J., Agostini M.L., Leist S.R., Schäfer A., Dinnon K.H., 3rd, Stevens L.J., et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci. Transl. Med. 2020;12:eabb5883.
    1. Shimo T., Maruyama R., Yokota T. In: Duchenne Muscular Dystrophy: Methods and Protocols. Bernardini C., editor. Springer; 2018. Designing Effective Antisense Oligonucleotides for Exon Skipping; pp. 143–155.
    1. Shiraki K., Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol. Ther. 2020;209:107512.
    1. Siegel D., Hui H.C., Doerffler E., Clarke M.O., Chun K., Zhang L., Neville S., Carra E., Lew W., Ross B., et al. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J. Med. Chem. 2017;60:1648–1661.
    1. Smith E.C., Denison M.R. Implications of altered replication fidelity on the evolution and pathogenesis of coronaviruses. Curr. Opin. Virol. 2012;2:519–524.
    1. Smith E.C., Blanc H., Surdel M.C., Vignuzzi M., Denison M.R. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog. 2013;9:e1003565.
    1. Snijder E.J., Bredenbeek P.J., Dobbe J.C., Thiel V., Ziebuhr J., Poon L.L.M., Guan Y., Rozanov M., Spaan W.J.M., Gorbalenya A.E. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J. Mol. Biol. 2003;331:991–1004.
    1. Snijder E.J., Decroly E., Ziebuhr J. The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing. Adv. Virus Res. 2016;96:59–126.
    1. Snijder E.J., Ronald W.A., de Wilde A.H., de Jong A.W.M., Zevenhoven-Dobbe J.C., Maier H.J., Frank F.G., Koster A.J., Bárcena M. A unifying structural and functional model of the coronavirus replication organelle: tracking down RNA synthesis. bioRxiv. 2020 2020.03.24.005298.
    1. Sola I., Mateos-Gomez P.A., Almazan F., Zuñiga S., Enjuanes L. RNA-RNA and RNA-protein interactions in coronavirus replication and transcription. RNA Biol. 2011;8:237–248.
    1. Sola I., Almazán F., Zúñiga S., Enjuanes L. Continuous and Discontinuous RNA Synthesis in Coronaviruses. Annu. Rev. Virol. 2015;2:265–288.
    1. Stein C.A., Castanotto D. FDA-Approved Oligonucleotide Therapies in 2017. Mol. Ther. 2017;25:1069–1075.
    1. Stuyver L.J., Whitaker T., McBrayer T.R., Hernandez-Santiago B.I., Lostia S., Tharnish P.M., Ramesh M., Chu C.K., Jordan R., Shi J., et al. Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture. Antimicrob. Agents Chemother. 2003;47:244–254.
    1. Subissi L., Imbert I., Ferron F., Collet A., Coutard B., Decroly E., Canard B. SARS-CoV ORF1b-encoded nonstructural proteins 12-16: replicative enzymes as antiviral targets. Antiviral Res. 2014;101:122–130.
    1. Subissi L., Posthuma C.C., Collet A., Zevenhoven-Dobbe J.C., Gorbalenya A.E., Decroly E., Snijder E.J., Canard B., Imbert I. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc. Natl. Acad. Sci. USA. 2014;111:E3900–E3909.
    1. Summerton J. Morpholino antisense oligomers: the case for an RNase H-independent structural type. Biochim. Biophys. Acta. 1999;1489:141–158.
    1. te Velthuis A.J.W., Arnold J.J., Cameron C.E., van den Worm S.H.E., Snijder E.J. The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent. Nucleic Acids Res. 2010;38:203–214.
    1. Thoms M., Buschauer R., Ameismeier M., Koepke L., Denk T., Hirschenberger M., Kratzat H., Hayn M., Mackens-Kiani T., Cheng J., et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020 doi: 10.1126/science.abc8665. Published online July 17, 2020.
    1. Urakova N., Kuznetsova V., Crossman D.K., Sokratian A., Guthrie D.B., Kolykhalov A.A., Lockwood M.A., Natchus M.G., Crowley M.R., Painter G.R., et al. β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome. J. Virol. 2018;92:e01965-17.
    1. Wang M., Cao R., Zhang L., Yang X., Liu J., Xu M., Shi Z., Hu Z., Zhong W., Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269–271.
    1. Wang Q., Wu J., Wang H., Gao Y., Liu Q., Mu A., Ji W., Yan L., Zhu Y., Zhu C., et al. Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase. Cell. 2020;182:417–428.
    1. Wang Y., Zhang D., Du G., Du R., Zhao J., Jin Y., Fu S., Gao L., Cheng Z., Lu Q., et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569–1578.
    1. Warren T.K., Jordan R., Lo M.K., Ray A.S., Mackman R.L., Soloveva V., Siegel D., Perron M., Bannister R., Hui H.C., et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381–385.
    1. Wong A.C.P., Li X., Lau S.K.P., Woo P.C.Y. Global Epidemiology of Bat Coronaviruses. Viruses. 2019;11:11.
    1. Wong G., Bi Y.-H., Wang Q.-H., Chen X.-W., Zhang Z.-G., Yao Y.-G. Zoonotic origins of human coronavirus 2019 (HCoV-19 / SARS-CoV-2): why is this work important? Zool. Res. 2020;41:213–219.
    1. Woo P.C.Y., Lau S.K.P., Lam C.S.F., Lau C.C.Y., Tsang A.K.L., Lau J.H.N., Bai R., Teng J.L.L., Tsang C.C.C., Wang M., et al. Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J. Virol. 2012;86:3995–4008.
    1. Xu X., Liu Y., Weiss S., Arnold E., Sarafianos S.G., Ding J. Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design. Nucleic Acids Res. 2003;31:7117–7130.
    1. Yates M.K., Seley-Radtke K.L. The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold. Antiviral Res. 2019;162:5–21.
    1. Yin W., Mao C., Luan X., Shen D.-D., Shen Q., Su H., Wang X., Zhou F., Zhao W., Gao M., et al. Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir. bioRxiv. 2020 2020.04.08.032763.
    1. Zhang Y., Gao Y., Wen X., Ma H. Current prodrug strategies for improving oral absorption of nucleoside analogues. Asian J. Pharm. Sci. 2014;9:65–74.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir