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      An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

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          Abstract

          A ribonucleoside analog inhibits SARS-CoV-2 in human airway epithelial cell cultures and SARS-CoV and MERS-CoV in mice.

          Catastrophic consequences

          Broad-spectrum antivirals are desirable, particularly in the context of emerging zoonotic infections for which specific interventions do not yet exist. Sheahan et al. tested the potential of a ribonucleoside analog previously shown to be active against other RNA viruses such as influenza and Ebola virus to combat coronaviruses. This drug was effective in cell lines and primary human airway epithelial cultures against multiple coronaviruses including SARS-CoV-2. Mouse models of SARS and MERS demonstrated that early treatment reduced viral replication and damage to the lungs. Mechanistically, this drug is incorporated into the viral RNA, inducing mutations and eventually leading to error catastrophe in the virus. In this manner, inducing catastrophe could help avoid catastrophe by stemming the next pandemic.

          Abstract

          Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show that the ribonucleoside analog β- d-N 4-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β- d-N 4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.

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          Most cited references36

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          Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

          In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
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            Virological assessment of hospitalized patients with COVID-2019

            Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.
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              Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.

              A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.
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                Author and article information

                Journal
                Sci Transl Med
                Sci Transl Med
                STM
                scitranslmed
                Science Translational Medicine
                American Association for the Advancement of Science
                1946-6234
                1946-6242
                29 April 2020
                : 12
                : 541
                : eabb5883
                Affiliations
                [1 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
                [2 ]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
                [3 ]Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
                [4 ]Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
                [5 ]Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
                [6 ]Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA 30322, USA.
                [7 ]Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA 30322, USA.
                [8 ]Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA.
                [9 ]Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
                [10 ]Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
                Author notes
                [*]

                These authors contributed equally to this work.

                []Corresponding author. Email: sheahan@ 123456email.unc.edu (T.P.S.); rbaric@ 123456email.unc.edu (R.S.B.)
                [‡]

                Present address: National Security Division, Pacific Northwest National Laboratory, Chemical and Biological Signature Sciences, Richland, WA 99352, USA.

                Author information
                http://orcid.org/0000-0001-9181-2183
                http://orcid.org/0000-0003-0178-4225
                http://orcid.org/0000-0002-8353-386X
                http://orcid.org/0000-0002-3143-6515
                http://orcid.org/0000-0001-7910-626X
                http://orcid.org/0000-0002-4989-5381
                http://orcid.org/0000-0002-4760-4923
                http://orcid.org/0000-0002-8942-1551
                http://orcid.org/0000-0003-4386-6958
                http://orcid.org/0000-0001-9935-1713
                http://orcid.org/0000-0001-5765-3406
                http://orcid.org/0000-0001-6919-2256
                http://orcid.org/0000-0003-3968-1862
                http://orcid.org/0000-0001-8012-5302
                http://orcid.org/0000-0001-9138-7578
                http://orcid.org/0000-0002-9803-8095
                http://orcid.org/0000-0003-3271-4174
                http://orcid.org/0000-0001-9726-8940
                http://orcid.org/0000-0001-7777-0773
                http://orcid.org/0000-0003-2655-0900
                http://orcid.org/0000-0001-6827-8701
                Article
                abb5883
                10.1126/scitranslmed.abb5883
                7199910
                32253226
                5c8abab2-642d-4662-845f-e8f2aafc8dd2
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 05 March 2020
                : 03 April 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: 5U19AI109680
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: 5R01AI132178
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI108197
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: HHSN272201500008C
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: 1U19AI142759
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: F31AI133952
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: T32AI112541
                Categories
                Research Article
                Research Articles
                STM r-articles
                Medicine
                Coronavirus
                Custom metadata
                Lindsey Pujanandez
                Kyle Solis

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