Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice
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Abstract
The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern with their potential to escape therapeutic monoclonal antibodies emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parental nucleoside of remdesivir, which targets the highly conserved RNA-dependent RNA polymerase. GS-621763 exhibited significant antiviral activity in lung cell lines and two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 significantly reduced viral load, lung pathology, and improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral currently in human clinical trial, proved both drugs to be similarly efficacious. These data demonstrate that therapy with oral prodrugs of remdesivir can significantly improve outcomes in SARS-CoV-2 infected mice. Thus, GS-621763 supports the exploration of GS-441524 oral prodrugs for the treatment of COVID-19 in humans.
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SciScore for 10.1101/2021.09.13.460111: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Mouse studies and in vivo infections: All mouse studies were performed at the University of North Carolina (Animal Welfare Assurance #A3410-01) using protocols (#20-059) approved by the University of North Carolina Institutional Animal Care and Use Committee. Sex as a biological variable not detected. Randomization For Matute-Bello scoring samples were blinded and three random fields of lung tissue were chosen and scored for the following: (A) neutrophils in alveolar space (none = 0, 1–5 cells = 1, > 5 cells = 2), (B) neutrophils in interstitial space (none = 0, 1–5 cells = 1, > 5 cells = 2), (C) hyaline membranes (none = 0, one membrane = 1, > 1 membrane = 2), (D) Proteinaceous debris in … SciScore for 10.1101/2021.09.13.460111: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Mouse studies and in vivo infections: All mouse studies were performed at the University of North Carolina (Animal Welfare Assurance #A3410-01) using protocols (#20-059) approved by the University of North Carolina Institutional Animal Care and Use Committee. Sex as a biological variable not detected. Randomization For Matute-Bello scoring samples were blinded and three random fields of lung tissue were chosen and scored for the following: (A) neutrophils in alveolar space (none = 0, 1–5 cells = 1, > 5 cells = 2), (B) neutrophils in interstitial space (none = 0, 1–5 cells = 1, > 5 cells = 2), (C) hyaline membranes (none = 0, one membrane = 1, > 1 membrane = 2), (D) Proteinaceous debris in air spaces (none = 0, one instance = 1, > 1 instance = 2), (E) alveolar septal thickening (< 2Å~ mock thickness = 0, 2–4Å~ mock thickness = 1, > 4Å~ mock thickness = 2). Blinding For Matute-Bello scoring samples were blinded and three random fields of lung tissue were chosen and scored for the following: (A) neutrophils in alveolar space (none = 0, 1–5 cells = 1, > 5 cells = 2), (B) neutrophils in interstitial space (none = 0, 1–5 cells = 1, > 5 cells = 2), (C) hyaline membranes (none = 0, one membrane = 1, > 1 membrane = 2), (D) Proteinaceous debris in air spaces (none = 0, one instance = 1, > 1 instance = 2), (E) alveolar septal thickening (< 2Å~ mock thickness = 0, 2–4Å~ mock thickness = 1, > 4Å~ mock thickness = 2). Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For virus titration by plaque assay, the caudal lobe of the right lung was homogenized in PBS, and the resulting homogenate was serial-diluted and inoculated onto confluent monolayers of Vero E6 cells, followed by agarose overlay. Vero E6suggested: RRID:CVCL_XD71)In vitro assays for antiviral activity: A549-hACE2 cells were plated at a density of 20,000 cells/well/100 μl in black-walled clear-bottom 96-well plates 24 hrs prior to infection. A549-hACE2suggested: RRID:CVCL_A5KB)Experimental Models: Organisms/Strains Sentences Resources Even groups (n=10, or less as indicated) of 10-week-old female BALB/c mice (Envigo; #047) were used in all in vivo efficacy studies. BALB/csuggested: NoneSoftware and Algorithms Sentences Resources Data was fit using a four-parameter non-linear regression analysis using Graphpad Prism. 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: We detected the following sentences addressing limitations in the study:Because of this caveat associated with our mouse model, the time in which to intervene with a direct acting antiviral and sufficiently improve outcomes is curtailed in mice as compared to humans. Our recent study with RDV exemplifies this where we found the degree of therapeutic benefit in mice infected with SARS-CoV-2 MA10 was dependent on the time of initiation (17). Here, we show that oral administration with GS-621763 prevents body weight loss, loss of pulmonary function, severe lung pathology and virus replication when administered at 12 and 24 hrs after infection. While we observed improvement in some metrics with RDV initiated at 24 hr in our prior studies (17), GS-621763 therapy initiated at a similar time comparatively improved all metrics assessed. Thus, herein we provide proof-of-concept preclinical data that the orally bioavailable ester analog of RDV GS-621763 can exert potent antiviral effects in vivo during an ongoing SARS-CoV-2 infection. Lastly, we show that GS-621763 therapy provides similar levels of protection from SARS-CoV-2 pathogenesis as MPV, an oral nucleoside analog prodrug effective against SARS-CoV-2 in mice that is currently in human clinical trials. Future directions are focused on extending these studies to evaluate the efficacy of combinations of antivirals in our models of SARS-CoV-2 pathogenesis and in other models that can evaluate the blockade of transmission such as hamster and ferret. In summary, we provide preclinical data demonstrating ...
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:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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Results from scite Reference Check: We found no unreliable references.
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