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A New Model of SARS-CoV-2 Infection Based on (Hydroxy) Chloroquine Activity

Robert J. Sheaff
doi: https://doi.org/10.1101/2020.08.02.232892
Robert J. Sheaff
Department of Chemistry and Biochemistry, The University of Tulsa, Tulsa, Oklahoma
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  • For correspondence: robert-sheaff@utulsa.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    CQ
    chloroquine
    HCQ
    hydroxychloroquine
    2DG
    2-deoxy glucose
    CTB
    CellTiterBlue
    CTG
    CellTiterGlo
    TCA
    TriCarboxylic Acid cycle
    ETC
    Electron Transport Chain
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted August 02, 2020.
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    A New Model of SARS-CoV-2 Infection Based on (Hydroxy) Chloroquine Activity
    Robert J. Sheaff
    bioRxiv 2020.08.02.232892; doi: https://doi.org/10.1101/2020.08.02.232892
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    A New Model of SARS-CoV-2 Infection Based on (Hydroxy) Chloroquine Activity
    Robert J. Sheaff
    bioRxiv 2020.08.02.232892; doi: https://doi.org/10.1101/2020.08.02.232892

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