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Review 1: "Protein glycosylation is essential for SARS-CoV-2 infection"

Reviewers: Anne Gleinich (The University of Georgia) | 📗📗📗📗◻️

Published onApr 14, 2022
Review 1: "Protein glycosylation is essential for SARS-CoV-2 infection"

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

The preprint “Protein glycosylation is essential for SARS-CoV-2 infection” describes a well-conceptualized study about the influence of the N-glycosylation machinery of the host on SARS-CoV-2 infection in vitro. This study categorizes basic research that applies translational approaches. 

Based on the current understanding of SARS-CoV-2 and its route of infection, this study explores antiviral treatment through pharmacologic intervention in vitro. Even though iminosugars and similar compounds have been considered or are already in use as antivirals (1), the presented work contributes evidence for a new treatment approach for SARS-CoV-2 infection in particular.

The authors tested ten inhibitors that inhibit a variety of steps in the N-glycosylation pathway in Vero E6 green monkey kidney epithelial cells (Vero E6) or human embryonic kidney 293 cells (HEK293). At least two of the compounds have been FDA-approved for the treatment of diseases such as Type II diabetes mellitus.

They found a significant and strong reduction of infected host cells for compounds that intervene with the early stages of the mammalian N-glycosylation pathway as well as minor effects on the viral infectivity for other compounds. The findings of the chemical inhibition were mirrored through siRNA knockdown of the corresponding key enzymes in the N-glycosylation pathway.

The overall study provides evidence that the SARS-CoV-2 infection is indeed dependent on the glycosylation of viral particles and demonstrates that a missing or faulty glycosylation pattern of the virions can prevent infection of host cells to a substantial degree in vitro

The manuscript would greatly benefit from expanding the discussion as well as experimental investigation regarding toxicity. The authors mention within the manuscript several times the importance of normal functioning of the host N-glycosylation machinery for viral infection. However, the manuscript is missing an adequate discussion of the possible implications (physiology, toxicity, changes in immune response, etc.) for the host if the N-glycosylation machinery is pharmacologically targeted – possibly considering the specific compounds and their mechanism of action. Especially, since pharmacological treatments leading to changes in the glycosylation pathway are not immediately cytotoxic. 

Similarly, the experimental test on a molecular level for cytotoxicity could be expanded. A cell that is busy degrading not only viral but its own misfolded proteins might not necessarily show strong signs of apoptosis within 2 days (also considering protein turnover rates). It might be worth testing the cell lysates of N-glycosylation inhibitor-treated cells for downregulation of anti-apoptotic or upregulation of apoptotic factors. Another option would be a more specific cell viability assay with t ≥ 48h. 

However, the broad and very diverse set of methods used in this study is noteworthy and substantiates the findings of the study from different angles.

Overall, this is a great study with convincing data but also with room for improvement on the design for controls.

The publication of this manuscript is recommended for (i) contributing new insights for understanding SARS-CoV-2 infection, and (ii) enabling the research community, including pharmaceutical companies, to investigate these novel findings on the next level.

REFERENCES

  1. Alonzi DS, Scott KA, Dwek RA, Zitzmann N. Iminosugar antivirals: the therapeutic sweet spot. Biochem Soc Trans. 2017 Apr 15;45(2):571-582. doi: 10.1042/BST20160182. PMID: 28408497; PMCID: PMC5390498.

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