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      Coronavirus genomic nsp14‐ExoN, structure, role, mechanism, and potential application as a drug target

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          Abstract

          The recent coronavirus disease 2019 (COVID‐19), causing a global pandemic with devastating effects on healthcare and social‐economic systems, has no special antiviral therapies available for human coronaviruses (CoVs). The severe acute respiratory syndrome coronavirus 2 (SARS‐Cov‐2) possesses a nonstructural protein (nsp14), with amino‐terminal domain coding for proofreading exoribonuclease (ExoN) that is required for high‐fidelity replication. The ability of CoVs during genome replication and transcription to proofread and exclude mismatched nucleotides has long hindered the development of anti‐CoV drugs. The resistance of SARS‐CoV‐2 to antivirals, especially nucleoside analogs (NAs), shows the need to identify new CoV inhibition targets. Therefore, this review highlights the importance of nsp14‐ExoN as a target for inhibition. Also, nucleoside analogs could be used in combination with existing anti‐CoV therapeutics to target the proofreading mechanism.

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          Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs.

          Kanchan Anand, John Ziebuhr, Parvesh Wadhwani … (2003)
          A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS). The viral main proteinase (Mpro, also called 3CLpro), which controls the activities of the coronavirus replication complex, is an attractive target for therapy. We determined crystal structures for human coronavirus (strain 229E) Mpro and for an inhibitor complex of porcine coronavirus [transmissible gastroenteritis virus (TGEV)] Mpro, and we constructed a homology model for SARS coronavirus (SARS-CoV) Mpro. The structures reveal a remarkable degree of conservation of the substrate-binding sites, which is further supported by recombinant SARS-CoV Mpro-mediated cleavage of a TGEV Mpro substrate. Molecular modeling suggests that available rhinovirus 3Cpro inhibitors may be modified to make them useful for treating SARS.
          Article 0 comments Cited 815 times – based on 0 reviews     Review now
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            Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys

            Travis Warren, Robert Jordan, Michael K Lo … (2016)
            Summary The most recent Ebola virus outbreak in West Africa – unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected – highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae 1 . No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we describe the discovery of a novel anti-EBOV small molecule antiviral, GS-5734, a monophosphoramidate prodrug of an adenosine analog. GS-5734 exhibits antiviral activity against multiple variants of EBOV in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternate substrate and RNA-chain terminator in primer-extension assays utilizing a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life = 14 h) and distribution to sanctuary sites for viral replication including testes, eye, and brain. In a rhesus monkey model of EVD, once daily intravenous administration of 10 mg/kg GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two of six treated animals. These results provide the first substantive, post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses – including filoviruses, arenaviruses, and coronaviruses – suggests the potential for expanded indications. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.
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              Continuous and Discontinuous RNA Synthesis in Coronaviruses.

              Isabel Sola, Fernando Almazan, Sonia Zuñiga … (2015)
              Replication of the coronavirus genome requires continuous RNA synthesis, whereas transcription is a discontinuous process unique among RNA viruses. Transcription includes a template switch during the synthesis of subgenomic negative-strand RNAs to add a copy of the leader sequence. Coronavirus transcription is regulated by multiple factors, including the extent of base-pairing between transcription-regulating sequences of positive and negative polarity, viral and cell protein-RNA binding, and high-order RNA-RNA interactions. Coronavirus RNA synthesis is performed by a replication-transcription complex that includes viral and cell proteins that recognize cis-acting RNA elements mainly located in the highly structured 5' and 3' untranslated regions. In addition to many viral nonstructural proteins, the presence of cell nuclear proteins and the viral nucleocapsid protein increases virus amplification efficacy. Coronavirus RNA synthesis is connected with the formation of double-membrane vesicles and convoluted membranes. Coronaviruses encode proofreading machinery, unique in the RNA virus world, to ensure the maintenance of their large genome size.
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                Author and article information

                Contributors
                Mohammed Tahir:
                ORCID: http://orcid.org/0000-0003-1588-469X
                mohammed.tahir@univsul.edu.iq
                Journal
                Journal ID (nlm-ta): J Med Virol
                Journal ID (iso-abbrev): J Med Virol
                Journal ID (doi): 10.1002/(ISSN)1096-9071
                Journal ID (publisher-id): JMV
                Title: Journal of Medical Virology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0146-6615
                ISSN (Electronic): 1096-9071
                Publication date (Electronic): 23 April 2021
                Publication date (Print): July 2021
                Volume: 93
                Issue: 7 , Special Issue on New coronavirus (2019‐nCoV or SARS‐CoV‐2) and the outbreak of the respiratory illness (COVID‐19): Part‐XIII ( doiID: 10.1002/jmv.v93.7 )
                Pages: 4258-4264
                Affiliations
                [ 1 ] Department of Biology University of Sulaimani Sulaimanyah Kurdistan Iraq
                Author notes
                [*] [* ] Correspondence Mohammed Tahir, Department of Biology, University of Sulaimani, Kurdistan, Sulaimanyah, Iraq.

                Email: mohammed.tahir@ 123456univsul.edu.iq

                Author information
                http://orcid.org/0000-0003-1588-469X
                Article
                Publisher ID: JMV27009
                DOI: 10.1002/jmv.27009
                PMC ID: 8250946
                PubMed ID: 33837972
                SO-VID: 79f3bb6d-6ca4-45f5-b533-dd18c8e95392
                Copyright © © 2021 Wiley Periodicals LLC
                License:

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                Date revision received : 07 April 2021
                Date received : 06 March 2021
                Date accepted : 08 April 2021
                Page count
                Figures: 3, Tables: 1, Pages: 7, Words: 4455
                Categories
                Subject: Review
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                cover-date July 2021
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:02.07.2021

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: coronavirus,exoribonuclease,nonstructural protein 14,proofreading,rna recombination
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: coronavirus, exoribonuclease, nonstructural protein 14, proofreading, rna recombination

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