Sheaff: A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity [HCQ]

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

Sheaff, R., bioRxiv, doi:10.1101/2020.08.02.232892 (Preprint) (In Vitro)

Sheaff, A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, , R., bioRxiv, doi:10.1101/2020.08.02.232892 (Preprint) (In Vitro)

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In Vitro study presenting a new theory on SARS-CoV-2 infection and why HCQ/CQ provides benefits, which potentially explains the observed relationships with smoking, diabetes, obesity, age, and treatment delay, and confirms the importance of accurate dosing. Metabolic analysis revealed HCQ/CQ inhibit oxidative phosphorylation in mitochondria (likely by sequestering protons needed to drive ATP synthase), inhibiting infection and/or slowing replication.

14 In Vitro studies support the efficacy of HCQ [Andreani, Clementi, Dang, Delandre, Faísca, Hoffmann, Liu, Ou, Purwati, Sheaff, Wang, Wang (B), Yao, Yuan].

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1. Andreani et al., Microbial Pathogenesis, doi:/10.1016/j.micpath.2020.104228, In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, https://www.sciencedirect.com/science/article/pii/S0882401020305155.

2. Clementi et al., Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704 (preprint 3/31), Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, https://www.frontiersin.org/articl..ign=ECO_FCIMB_XXXXXXXX_auto-dlvrit.

3. Dang et al., bioRxiv, doi:10.1101/2021.03.16.435741, Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein, https://www.biorxiv.org/content/10.1101/2021.03.16.435741v1.

4. Delandre et al., Pharmaceuticals, doi:10.3390/ph15040445, Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, https://www.mdpi.com/1424-8247/15/4/445.

5. Faísca et al., Pharmaceutics, doi:10.3390/pharmaceutics14040877, Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2, https://www.mdpi.com/1999-4923/14/4/877.

6. Hoffmann et al., Nature, (2020), doi:10.1038/s41586-020-2575-3, Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, https://www.nature.com/articles/s41586-020-2575-3.

7. Liu et al., Cell Discovery 6, 16 (2020), doi:10.1038/s41421-020-0156-0, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, https://www.nature.com/articles/s41421-020-0156-0.

8. Ou et al., PLOS Pathogens, doi:10.1371/journal.ppat.1009212 (preprint 7/22), Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, https://journals.plos.org/plospath..le?id=10.1371/journal.ppat.1009212.

9. Purwati et al., PLOS One, doi:10.1371/journal.pone.0252302, An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, https://journals.plos.org/plosone/..le?id=10.1371/journal.pone.0252302.

10. Sheaff, R., bioRxiv, doi:10.1101/2020.08.02.232892, A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, https://www.biorxiv.org/content/10.1101/2020.08.02.232892v1.

11. Wang et al., Phytomedicine, doi:10.1016/j.phymed.2020.153333, Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467095/.

12. Wang (B) et al., Cell Res. 30, 269–271, doi:L10.1038/s41422-020-0282-0, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, https://www.nature.com/articles/s4..iVs8_7R1KkwOuqjRhx7psfHV6iSDRD1cM0.

13. Yao et al., Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237, In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), https://academic.oup.com/cid/advan..le/doi/10.1093/cid/ciaa237/5801998.

14. Yuan et al., Communications Biology, doi:10.1038/s42003-022-03841-8, Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, https://www.nature.com/articles/s42003-022-03841-8.

Sheaff et al., 2 Aug 2020, preprint, 1 author.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

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Abstract: bioRxiv preprint doi: https://doi.org/10.1101/2020.08.02.232892; this version posted August 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Sheaff, 2020 A New Model of SARS-CoV-2 Infection Based on (Hydroxy) Chloroquine Activity Robert J. Sheaff Department of Chemistry and Biochemistry, The University of Tulsa, Tulsa, Oklahoma 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. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.02.232892; this version posted August 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Sheaff, 2020

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