The Preclinical Inhibitor GS441524 in Combination with GC376 Efficaciously Inhibited the Proliferation of SARS-CoV-2 in the Mouse Respiratory Tract
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Abstract
The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.
Importance
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has seriously threatened global public health and economic development. Currently, effective therapies to treat COVID-19 are urgently needed. In this study, we assessed the efficacy of the preclinical inhibitors GC376 and GS441524 using a mouse-adapted SARS-CoV-2 infected mouse model for the first time. Our results showed that low-dose combined application of GC376 and GS441524 could effectively protect mice from HRB26M infection in the upper and lower respiratory tracts. Hence, the combined application should be developed and considered for future clinic practice.
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SciScore for 10.1101/2020.11.12.380931: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The toxicity studies in mice and single-dose PK study in SD rats were performed using protocols that were approved by the Scientific Ethics Committee of Huazhong Agricultural University. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Specific pathogen-free female BALB/c mice, aged 4-6 weeks were obtained from Beijing Vital River Laboratory Animal Technologies Co., Ltd (Beijing, China) and were housed and bred in the temperature-, humidity- and light cycle-controlled animal facility (20 ± 2 °C; 50 ± 10%; light, 7:00–19:00; dark, 19:00–7:00, respectively) of the Animal Center, Academy of Military Medical … SciScore for 10.1101/2020.11.12.380931: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The toxicity studies in mice and single-dose PK study in SD rats were performed using protocols that were approved by the Scientific Ethics Committee of Huazhong Agricultural University. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Specific pathogen-free female BALB/c mice, aged 4-6 weeks were obtained from Beijing Vital River Laboratory Animal Technologies Co., Ltd (Beijing, China) and were housed and bred in the temperature-, humidity- and light cycle-controlled animal facility (20 ± 2 °C; 50 ± 10%; light, 7:00–19:00; dark, 19:00–7:00, respectively) of the Animal Center, Academy of Military Medical Sciences, Beijing. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Briefly, Vero E6 cells were seeded in 96-well plates with opaque walls. Vero E6suggested: NoneExperimental Models: Organisms/Strains Sentences Resources In vivo toxicity study of GC376 and GS441524: The toxicity studies were performed in 4- to 6-week-old female BALB/c mice. BALB/csuggested: RRID:IMSR_ORNL:BALB/cRl)Software and Algorithms Sentences Resources Manual model rebuilding and refinement were performed using COOT (42) and the PHENIX software suite. COOTsuggested: (Coot, RRID:SCR_014222)PHENIXsuggested: (Phenix, RRID:SCR_014224)Structural figures were generated using PyMOL (Schrödinger). PyMOLsuggested: (PyMOL, RRID:SCR_000305)The data were analyzed using Microsoft Excel 2016 and GraphPad Prism 7.0. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)The data were analyzed using Microsoft Excel 2016 and GraphPad Prism 7.0. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)Results from OddPub: Thank you for sharing your data.
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: Please consider improving the rainbow (“jet”) colormap(s) used on page 29. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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