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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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Zinc for COVID-19

2nd treatment shown to reduce risk in July 2020

^*, now with p = 0.00000064 from 45 studies, recognized in 17 countries.

Lower risk for mortality, ventilation, hospitalization, progression, recovery, and viral clearance.

No treatment is 100% effective. Protocols combine treatments. ^* >10% efficacy, ≥3 studies.

4,500+ studies for 81 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.

10 preclinical studies support the efficacy of zinc for COVID-19:

5 In Silico studies1-5

4 In Vitro studies3,6-8

1 In Vivo animal study3

Important missing comments or errors? Let us know.

Study covers metformin and zinc.

1. 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.

2. 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.

3. El-Megharbel et al., Chemical and spectroscopic characterization of (Artemisinin/Quercetin/ Zinc) novel mixed ligand complex with assessment of its potent high antiviral activity against SARS-CoV-2 and antioxidant capacity against toxicity induced by acrylamide in male rats, PeerJ, doi:10.7717/peerj.15638.peerj.com, doi.org.

4. Bess et al., Identification of oral therapeutics using an AI platform against the virus responsible for COVID-19, SARS-CoV-2, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1297924.frontiersin.org, doi.org.

5. Pormohammad et al., Zinc and SARS-CoV-2: A molecular modeling study of Zn interactions with RNA-dependent RNA-polymerase and 3C-like proteinase enzymes, International Journal of Molecular Medicine, doi:10.3892/ijmm.2020.4790.spandidos-publications.com, doi.org.

6. Hajdrik et al., In Vitro Determination of Inhibitory Effects of Humic Substances Complexing Zn and Se on SARS-CoV-2 Virus Replication, Foods, doi:10.3390/foods11050694.mdpi.com, doi.org.

7. Panchariya et al., Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro, Chemical Communications, doi:10.1039/D1CC03563K.rsc.org, doi.org.

8. te Velthuis et al., Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture, PLOS Pathogens 2010, 6:11, doi:10.1371/journal.ppat.1001176.plos.org, 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 Zinc 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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