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Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

Lockwood, T., BioMetals, doi:10.1007/s10534-024-00590-5

Apr 2024

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Metformin for COVID-19

3rd treatment shown to reduce risk in July 2020, now with p < 0.00000000001 from 98 studies.

Lower risk for mortality, ventilation, ICU admission, hospitalization, progression, and recovery.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 110 treatments. c19early.org

In Silico analysis suggesting potential benefits of metformin and zinc for COVID-19. Author proposes that metformin can form a complex with zinc ions, increasing zinc bioavailability, and that the metformin-zinc complex may slow viral multiplication, viral invasion, and pathogenic host inflammation by inhibiting the SARS-CoV-2 main protease, papain-like protease, and various host proteases responsive to zinc, allowing time for immunity to clear the infection.

12 preclinical studies support the efficacy of metformin for COVID-19:

3 In Silico studies1-3

6 In Vitro studies1,4-8

3 In Vivo animal studies4,6,9

A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI)10. Metformin inhibits SARS-CoV-2 in vitro7,8, minimizes LPS-induced cytokine storm in a mouse model9, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS6, may protect against SARS-CoV-2-induced neurological disorders5, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation11, reduces UUO and FAN-induced kidney fibrosis6, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells6, may reduce inflammation, oxidative stress, and thrombosis via regulating glucose metabolism1, attenuates spike protein S1-induced inflammatory response and α-synuclein aggregation4, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity12.

Important missing comments or errors? Let us know.

Study covers metformin and zinc.

1. Hou et al., Metformin is a potential therapeutic for COVID-19/LUAD by regulating glucose metabolism, Scientific Reports, doi:10.1038/s41598-024-63081-0.nature.com, doi.org.

2. Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.scienceopen.com, doi.org.

3. Lockwood, T., Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent, BioMetals, doi:10.1007/s10534-024-00590-5.springer.com, doi.org.

4. Chang et al., SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin, Biomedicines, doi:10.3390/biomedicines12061223.mdpi.com, doi.org.

5. Yang et al., SARS-CoV-2 infection causes dopaminergic neuron senescence, Cell Stem Cell, doi:10.1016/j.stem.2023.12.012.sciencedirect.com, doi.org.

6. Miguel et al., Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney, Redox Biology, doi:10.1016/j.redox.2023.102957.sciencedirect.com, doi.org.

7. Ventura-López et al., Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial, Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113223.sciencedirect.com, doi.org.

8. Parthasarathy et al., Metformin Suppresses SARS-CoV-2 in Cell Culture, bioRxiv, doi:10.1101/2021.11.18.469078.biorxiv.org, doi.org.

9. Taher et al., Anti‑inflammatory effect of metformin against an experimental model of LPS‑induced cytokine storm, Experimental and Therapeutic Medicine, doi:10.3892/etm.2023.12114.spandidos-publications.com, doi.org.

10. Wang et al., Effects of metformin on acute respiratory distress syndrome in preclinical studies: a systematic review and meta-analysis, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1215307.frontiersin.org, doi.org.

11. Zhang et al., SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects, Pathogens, doi:10.3390/pathogens13010075.mdpi.com, doi.org.

12. Petakh et al., Metformin Alters mRNA Expression of FOXP3, RORC, and TBX21 and Modulates Gut Microbiota in COVID-19 Patients with Type 2 Diabetes, Viruses, doi:10.3390/v16020281.mdpi.com, doi.org.

Lockwood et al., 5 Apr 2024, peer-reviewed, 1 author. Contact: thomas.lockwood@wright.edu.

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

This Paper Metformin All

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

Thomas D Lockwood

BioMetals, doi:10.1007/s10534-024-00590-5

Independent trials indicate that either oral Zn 2+ or metformin can separately improve COVID-19 outcomes by approximately 40%. Coordination chemistry predicts a mechanistic relationship and therapeutic synergy. Zn 2+ deficit is a known risk factor for both COVID-19 and non-infectious inflammation. Most dietary Zn 2+ is not absorbed. Metformin is a naked ligand that presumably increases intestinal Zn 2+ bioavailability and active absorption by cation transporters known to transport metformin. Intracellular Zn 2+ provides a natural buffer of many protease reactions; the variable "set point" is determined by Zn 2+ regulation or availability. A Zn 2+ -interactive protease network is suggested here. The two viral cysteine proteases are therapeutic targets against COVID-19. Viral and many host proteases are submaximally inhibited by exchangeable cell Zn 2+ . Inhibition of cysteine proteases can improve COVID-19 outcomes and non-infectious inflammation. Metformin reportedly enhances the natural moderating effect of Zn 2+ on bioassayed proteome degradation. Firstly, the dissociable metformin-Zn 2+ complex could be actively transported by intestinal cation transporters; thereby creating artificial pathways of absorption and increased body Zn 2+ content. Secondly, metformin Zn 2+ coordination can create a non-natural protease inhibitor independent of cell Zn 2+ content. Moderation of peptidolytic reactions by either or both mechanisms could slow (a) viral multiplication (b) viral invasion and (c) the pathogenic host inflammatory response. These combined actions could allow development of acquired immunity to clear the infection before life-threatening inflammation. Nirmatrelvir (Paxlovid®) opposes COVID-19 by selective inhibition the viral main protease by a Zn 2+ -independent mechanism. Pending safety evaluation, predictable synergistic benefits of metformin and Zn 2+ , and perhaps metformin/Zn 2+ /Paxlovid® co-administration should be investigated.

Author contributions T.D.L. wrote the manuscript Declarations Conflict of interest There are no conflicting interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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