A New Model of SARS-CoV-2 Infection Based on (Hydroxy) Chloroquine Activity
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Abstract
Chloroquine and hydroxychloroquine (H)CQ are well known anti-malarial drugs, while their use against COVID-19 is more controversial. (H)CQ activity was examined in tissue culture cells to determine if their anti-viral benefits or adverse effects might be due to altering host cell pathways. Metabolic analysis revealed (H)CQ inhibit oxidative phosphorylation in mitochondria, likely by sequestering protons needed to drive ATP synthase. This activity could cause cardiotoxicity because heart muscle relies on beta oxidation of fatty acids. However, it might also explain their therapeutic benefit against COVID-19. A new model of SARS-CoV-2 infection postulates virus enters host cell mitochondria and uses its protons for genome release. Oxidative phosphorylation is eventually compromised, so glycolysis is upregulated to maintain ATP levels. (H)CQ could prevent viral infection and/or slow its replication by sequestering these protons. In support of this model other potential COVID-19 therapeutics also targeted mitochondria, as did tobacco smoke, which may underlie smokers’ protection. The mitochondria of young people are naturally more adaptable and resilient, providing a rationale for their resistance to disease progression. Conversely, obesity and diabetes could exacerbate disease severity by providing extra glucose to infected cells dependent on glycolysis. The description of (H)CQ function presented here, together with its implications for understanding SARS-CO-V2 infection, makes testable predictions about disease progression and identifies new approaches for treating COVID-19.
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SciScore for 10.1101/2020.08.02.232892: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell Culture: The following immortalized cell lines were obtained from the American Tissue Culture Collection: H293 kidney epithelial cells, HDFs (human diploid fibroblasts immortalized by telomerase expression), and U549 lung carcinoma cells. U549suggested: Coriell Cat# GM23466, RRID:CVCL_U549)29 Briefly, 2.5×106 h293 cells were re-suspended in 1ml L1-5 media without and with 20mM glucose. h293suggested: RRID:CVCL_H293)Smoke exposure: … SciScore for 10.1101/2020.08.02.232892: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell Culture: The following immortalized cell lines were obtained from the American Tissue Culture Collection: H293 kidney epithelial cells, HDFs (human diploid fibroblasts immortalized by telomerase expression), and U549 lung carcinoma cells. U549suggested: Coriell Cat# GM23466, RRID:CVCL_U549)29 Briefly, 2.5×106 h293 cells were re-suspended in 1ml L1-5 media without and with 20mM glucose. h293suggested: RRID:CVCL_H293)Smoke exposure: Four p60mm plates of attached A549 lung carcinoma cells were aspirated, washed with PBS, and aspirated again. A549suggested: NCI-DTP Cat# A549, RRID:CVCL_0023)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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.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.
- No funding statement was detected.
- No protocol registration statement was detected.
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