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Review 3: "Inhibiting Glutamine Metabolism Blocks Coronavirus Replication in Mammalian Cells"

Overall, the study highlights the essential role of glutamine metabolism for coronavirus infection and potential of targeting it as an antiviral strategy.

Published onNov 03, 2023
Review 3: "Inhibiting Glutamine Metabolism Blocks Coronavirus Replication in Mammalian Cells"
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key-enterThis Pub is a Review of
Inhibiting Glutamine Metabolism Blocks Coronavirus Replication in Mammalian Cells
Inhibiting Glutamine Metabolism Blocks Coronavirus Replication in Mammalian Cells
Description

Abstract Developing therapeutic strategies against COVID-19 has gained widespread interest given the likelihood that new viral variants will continue to emerge. Here we describe one potential therapeutic strategy which involves targeting members of the glutaminase family of mitochondrial metabolic enzymes (GLS and GLS2), which catalyze the first step in glutamine metabolism, the hydrolysis of glutamine to glutamate. We show three examples where GLS expression increases during coronavirus infection of host cells, and another in which GLS2 is upregulated. The viruses hijack the metabolic machinery responsible for glutamine metabolism to generate the building blocks for biosynthetic processes and satisfy the bioenergetic requirements demanded by the ‘glutamine addiction’ of virus-infected host cells. We demonstrate how genetic silencing of glutaminase enzymes reduces coronavirus infection and that newer members of two classes of small molecule allosteric inhibitors targeting these enzymes, designated as SU1, a pan-GLS/GLS2 inhibitor, and UP4, which is specific for GLS, block viral replication in mammalian epithelial cells. Overall, these findings highlight the importance of glutamine metabolism for coronavirus replication in human cells and show that glutaminase inhibitors can block coronavirus infection and thereby may represent a novel class of anti-viral drug candidates.Teaser Inhibitors targeting glutaminase enzymes block coronavirus replication and may represent a new class of anti-viral drugs.

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: 

In their research article, the authors assert that glutamine metabolism plays an important role in the replication of the coronavirus virus family within mammalian cell systems. Employing transcriptomics, proteomics, and metabolomics methodologies, their study reveals a compelling positive correlation between heightened glutamine metabolism and the replication of coronaviruses. 

Major concerns: 

The overall quality of the uploaded figures is problematic, which significantly decrease the clarity and comprehensibility of the review. Several issues with specific figures further compound these problems, including:

  • Figures 1A and 1B display blurry and pixelated patterns.

  • Figure 1D is cut off at one edge, and the legends fail to elucidate the significance of numbers 1 and 8.

  • Figure 1H lacks a length scale for microscopic observations.

  • Figure 1L is lacking a legend.

  • Figure 4I requires re-uploading at a higher resolution.

Moreover, specific claims within the figures and text require critical attention:
In Figure 1D, the justification for the lack of GSL2 expression is problematic. Given that HBEC are bronchial epithelial cells and GSL2 is predominantly expressed in the liver, pancreas, and brain, it is expected to have low to no expression in pulmonary tissues. This needs to be justified in a better way. 

For Figures 1E and 1G, it is evident that the authors did not conduct statistical analyses prior to drawing their conclusions. The absence of statistical rigor weakens the overall scientific validity.

Figures 1J and 1K are cited in the text to demonstrate the temporal RNA transcript levels association between GLS transcripts and viral transcripts OC43. However, a discrepancy arises in Figure 1J and 1K, where GLS RNA levels and viral RNA do not overlap at 12hpi. This result necessitates a detailed justification.

Figure 4J is discussed in the text as showing the effects of UP4 treatment on various parameters. The description mentions the abolition of the increases in glutamate, downstream TCA cycle intermediates, and aspartate during OC43 infection, as well as nucleosides and nucleotides. However, upon careful examination of the heatmap, it becomes clear that only nucleosides exhibit an abolition of the increase in the infected +UP4 conditions. This observation should be reflected in the figure's description.

Minor Concerns

  • The absence of line numbers in the preprint is making it challenging for reviewers to provide precise feedback or point out specific concerns. Adding line numbers to the document would facilitate the review process.

  • Figure 1M: The preprint mentioned Figure 1M in the figure legend, but the figure itself is missing. To ensure completeness and consistency, it's crucial to include Figure 1M as described in the legend.

  • Figure 4J Experiment Design: It's suggested that the experiment design for Figure 4J could benefit from including a control uninfected condition with UP4 to understand the impact of UP4 on uninfected cells. 

Comments
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ulna operating:

The effects of the UP4 therapy on several basketball stars parameters are illustrated in Figure 4J, which is cited in the text.