The adenosine analogue prodrug ATV006 is orally bioavailable and has potent preclinical efficacy against SARS-CoV-2 and its variants

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   ScreenIT

   Oct 22, 2021

   SciScore for 10.1101/2021.10.13.463130: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   Ethics	IACUC: All animal studies protocols were approved by the Animal Welfare Committee and all procedures used in animal studies complied with the guidelines and policies of the Animal Care and Use Committee.
   Sex as a biological variable	PK study in rat: Male SD rats (180-220 g, N = 3) were fasted for 12 h before drug administration.
   Randomization	not detected.
   Blinding	not detected.
   Power Analysis	not detected.
   Cell Line Authentication	not detected.

   Table 2: Resources

   Antibodies
   Sentences	Resources
   Cells were then incubated with a rabbit anti-SARS-CoV-2 nucleocapsid protein polyclonal antibody (Cat. No.: 40143-T62, Sino Biological), followed by an HRP-labeled goat anti-rabbit secondary antibody (Cat. No.: …

   SciScore for 10.1101/2021.10.13.463130: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   Ethics	IACUC: All animal studies protocols were approved by the Animal Welfare Committee and all procedures used in animal studies complied with the guidelines and policies of the Animal Care and Use Committee.
   Sex as a biological variable	PK study in rat: Male SD rats (180-220 g, N = 3) were fasted for 12 h before drug administration.
   Randomization	not detected.
   Blinding	not detected.
   Power Analysis	not detected.
   Cell Line Authentication	not detected.

   Table 2: Resources

   Antibodies
   Sentences	Resources
   Cells were then incubated with a rabbit anti-SARS-CoV-2 nucleocapsid protein polyclonal antibody (Cat. No.: 40143-T62, Sino Biological), followed by an HRP-labeled goat anti-rabbit secondary antibody (Cat. No.: 109-035-088, Jackson Immuno Research Laboratories).	anti-SARS-CoV-2 nucleocapsid protein suggested: None anti-rabbit suggested: None
   Experimental Models: Cell Lines
   Sentences	Resources
   HEK 293T cells were obtained from American Tissue Culture Collection (	HEK 293T suggested: CCLV Cat# CCLV-RIE 1018, RRID:CVCL_0063)
   African green monkey kidney Vero E6 cell line (Vero E6) was kindly provided by Dr. Hui Zhang (Sun Yat-sen University)	Vero E6 suggested: RRID:CVCL_XD71)
   Anti-SARS-CoV-2 activity assays: Vero E6 and Huh7 cells were seeded at 2 × 104 cells per well in 48-well plates.	Huh7 suggested: None
   Experimental Models: Organisms/Strains
   Sentences	Resources
   PK study in rat: Male SD rats (180-220 g, N = 3) were fasted for 12 h before drug administration.	SD suggested: None
   Tissue distribution study in mice: Five C57BL/6 mice were fasted for 12-16 h before administered orally with a single dose of 100 mg/kg ATV006.	C57BL/6 suggested: None
   Recombinant DNA
   Sentences	Resources
   In brief, the cells in 24-well plate transfected with 500 ng pBAC-SARS-CoV-2-Replicon-Luciferase plasmid and 10 ng RL-TK plasmid.	pBAC-SARS-CoV-2-Replicon-Luciferase suggested: None RL-TK suggested: None
   Software and Algorithms
   Sentences	Resources
   Multiple sequences alignments were performed using the progressive method (FFT-NS-2) implemented in MAFFT (version 7.4) (Katoh et al. 2002).	MAFFT suggested: (MAFFT, RRID:SCR_011811)
   The whole genome mutation analysis was carried out used the pipeline provided by CoVa (Ali. et al. 2021) (version 0.2) software.	CoVa suggested: (COVA, RRID:SCR_005175)
   Finally, the ggplot2 was used for drawing in R.	ggplot2 suggested: (ggplot2, RRID:SCR_014601)
   Data analysis was performed with GraphPad Prism Software (GraphPad Software Inc.	GraphPad Prism suggested: (GraphPad Prism, RRID:SCR_002798) GraphPad suggested: (GraphPad Prism, RRID:SCR_002798)

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   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).

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   Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

   To address this issue, herein, we synthesized a series of SCFA and amino acid prodrug of 69-0 aiming at overcoming its limitations. Among the compounds synthesized, the isobutyryl adenosine analogue ATV006 had improved oral absorption and potently inhibited the replication of SARS-CoV-2, especially the Delta variant (Fig 2). Compared to remdesivir, ATV006 is structurally simpler and easier to synthesize via a three-step transformation with 69-0 as starting material, which would reduce the cost and accelerate mass production. In addition, the orally active ATV006 is potentially more useful for the management of SARS-CoV-2 infection at the early stage. After oral administration of ATV006, it is rapidly hydrolyzed by cellular esterases to produce the parent nucleoside 69-0 (Hsu et al. 2003; Lavis 2008), which then undergoes three steps of phosphorylation and is transformed to the active triphosphate form (Fig 3C), the same active component as that of remdesivir. Therefore, ATV006 shares the same mechanism of stalling SARS-CoV-2 polymerase as that of remdesivir (Kokic et al. 2021; Mackman et al. 2021; Wei et al. 2021; Yin et al. 2020a). Several other small-molecule anti-SARS-CoV-2 antivirals are also under development, including the ones that block viral entry, inhibit Mpro, and target host immunity (Faheem et al. 2020; Good et al. 2021; Kabinger et al. 2021; Li et al. 2021; Minghua et al. 2021; Pruijssers et al. 2020; Sabbah et al. 2021; Vuong et al. 2021; Wahl et al. 2021; Zhan...

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   Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
   

   Identifier	Status	Title
   NCT04405570	Completed	A Safety, Tolerability and Efficacy of Molnupiravir (EIDD-28…

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   Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

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   Results from JetFighter: We did not find any issues relating to colormaps.

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   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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   Results from scite Reference Check: We found no unreliable references.

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   Version published to 10.1101/2021.10.13.463130v1 on bioRxiv

   Oct 14, 2021