An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
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Abstract
Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, 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 coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (b-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. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo , all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
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SciScore for 10.1101/2020.03.19.997890: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources To measure cell viability to determine if there was any NHC induced cytotoxicity, Calu3 2B4 cells were plated and treated with NHC only as described above. Calu3 2B4suggested: RRID:CVCL_YZ47)Briefly, 500,000 Vero E6 cells/well were seeded in 6-well plates. Vero E6suggested: NoneThird, to titer lungs by plaque assay, Vero CCL81 cells were used and plaques were enumerated 3 days post infection. Vero CCL81suggested: NoneExperimental Models: Organisms/Strains Sentences Resources For SARS-CoV, in cohorts of equivalent numbers of male and female 20-29 week old SPF C57BL/6J (Stock 000664 … SciScore for 10.1101/2020.03.19.997890: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources To measure cell viability to determine if there was any NHC induced cytotoxicity, Calu3 2B4 cells were plated and treated with NHC only as described above. Calu3 2B4suggested: RRID:CVCL_YZ47)Briefly, 500,000 Vero E6 cells/well were seeded in 6-well plates. Vero E6suggested: NoneThird, to titer lungs by plaque assay, Vero CCL81 cells were used and plaques were enumerated 3 days post infection. Vero CCL81suggested: NoneExperimental Models: Organisms/Strains Sentences Resources For SARS-CoV, in cohorts of equivalent numbers of male and female 20-29 week old SPF C57BL/6J (Stock 000664 Jackson Labs) mice (n = 10/dose group), we administered vehicle (10% PEG, 2.5% Cremophor RH40 in water) or 50, 150 or 500mg/kg EIDD-2801 by oral gavage 2hr prior to intranasal infection with 1E+04 PFU mouse-adapted SARS-CoV strain MA15 in 50μl. C57BL/6Jsuggested: NoneWe performed all in vivo studies with EIDD-2801 in equivalent numbers of 10-14 week old female and male C57BL/6J hDPP4 mice. C57BL/6J hDPP4suggested: NoneSoftware and Algorithms Sentences Resources Data was analyzed using GraphPad Prism 8.0 (La Jolla, CA). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)The RUBY package viral_seq version 1.0.6 (https://rubygems.org/gems/viral_seq) was used to calculate the mutation rate at each position. viral_seqsuggested: (viral_seq, RRID:SCR_018515)Amino acid conservation scores of coronavirus RdRp were generated using ConSurf Server (https://consurf.tau.ac.il/) using the protein alignment described above and visualized on the SARS-CoV RdRp structure (PDB: 6NUR) in PyMol (version 1.8.6.0)20,52. PyMolsuggested: (PyMOL, RRID:SCR_000305)Statistical analysis: All statistical data analyses were performed in Graphpad Prism 8. Graphpad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
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- No protocol registration statement was detected.
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