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Review 1: "Astodrimer sodium, dendrimer antiviral, inhibits replication of SARS-CoV-2 in vitro"

Published onOct 20, 2020
Review 1: "Astodrimer sodium, dendrimer antiviral, inhibits replication of SARS-CoV-2 in vitro"
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key-enterThis Pub is a Review of
Virucidal and antiviral activity of astodrimer sodium against SARS-CoV-2 in vitro
Description

AbstractAn effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral and virucidal activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 and Calu-3 cells, with 50% effective concentrations (EC50) for i) reducing virus-induced cytopathic effect of 0.002 to 0.012 mg/mL in Vero E6 cells, and ii) infectious virus release by plaque assay of 0.019 to 0.031 mg/mL in Vero E6 cells and 0.031 to 0.045 mg/mL in Calu-3 cells. The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also virucidal, reducing SARS-CoV-2 infectivity by >99.9% (>3 log10) within 1 minute of exposure, and up to >99.999% (>5 log10) shown at astodrimer sodium concentrations of 10 to 30 mg/mL in Vero E6 and Calu-3 cell lines. Astodrimer sodium also inhibited infection in a primary human airway epithelial cell line. The data were similar for all investigations and were consistent with the potent antiviral and virucidal activity of astodrimer sodium being due to inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial attachment of the virus to the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a nasally administered or inhaled antiviral agent for SARS-CoV-2 prevention and treatment applications.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The manuscript contains information about the in-vitro antiviral activity against SARS-CoV-2 of a drug already on the market in Australia, New Zealand, Asia, and Europe in a vaginal gel and its potential reformulation into a nasal spray for the prevention and treatment of COVID-19.

Even though the experimental protocol used to determine viral inactivation in Vero cells has been already published in the literature by other researchers, who are properly cited by the authors, the reported results support a potential advancement in COVID-19 prevention and treatment, as the authors affirm. However, claims included in the manuscript have varying strengths of evidence based on the methods and data:

  • The statement “Astodrimer sodium inhibits replication of SARS-CoV-2 in vitro” is very well-supported by the data and methods used. Decision-makers should consider this claim actionable without reservation based on the methods and data provided.

  • The statement “Astodrimer sodium has an EC50 between 0.09 – 0.742 and high SI regarding cytopathic effect inhibition when added 1 hour before or after infection with SARS-CoV-2” is generally supported by the data and methods used. I would report the experimental data in the “RESULTS” section, but I would rather report this in the following way in the ABSTRACT and DISCUSSION: “Astodrimer sodium has an EC50 at low micromolar concentration and high SI regarding cytopathic effect inhibition when added 1 hour before or after infection with SARS-CoV-2, even if SARS-CoV-2 is treated with astodrimer sodium prior to infection”. This latter claim would be very well supported by the data and methods used considering the experimental uncertainty of this type of method. If reported as suggested, this claim becomes very well-supported by the data and methods used and decision-makers should consider the claims in this study actionable without reservation based on the methods and data.


  • The statement: “The complete abolition of virus infection at all time points in the TOA assay are also consistent with astodrimer sodium being a potent antiviral agent that inhibits the early phase of virus infection and replication” is generally supported, but needs further discussion about the reason why Remdesivir showed poor antiviral action in this study. This is not expected and could render the results needing further confirmation because Remdesivir is used at a concentration considered inhibitory. I think this apparently contradictory finding needs some additional comment.


  • The statement “Astodrimer is already on the market as a drug in a vaginal gel and may be formulated into a nasal spray potentially useful for the prevention and treatment of COVID-19” is generally supported by the data and methods used. I would recommend adding some more details regarding the pathway between these findings and the use of astodrimer sodium as an active ingredient in nasal formulations, such as ciliotoxicity and local tolerance studies prior to clinical trials. These properties are not only linked to the formulation, but to astodrimer sodium, as well.

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