randombio.com | commentary
Tuesday, April 07, 2020

Debunking the zinc-coronavirus myth

The idea that chloroquine is a zinc ionophore that acts through zinc is based on misreading a single bad paper

I 'm delighted that people are finally reading the scientific literature, and that they finally have the time to do it. And it's great that journals are making these articles free for the public to read. It's something I've advocated for years. Now if we could only convince people to read a little more skeptically.

I'm talking about the idea that zinc and chloroquine are a treatment for coronavirus. Chloroquine by itself might be, and zinc is certainly good for you—I took a zinc tablet once about six months ago myself—I didn't like it—but the idea that chloroquine acts through zinc just has no experimental support.

The reference they cite is an article in PLoS Pathogens by Te Veltuis et al.[1] The authors claim zinc pyrithione inhibits RNA virus replication by inhibiting the replication and transcription complex. Unfortunately, these guys are actually talking about pyrithione, which is a zinc ionophore, or at least a chelator, and a darn good one, and they don't even mention chloroquine.

If that molecule sounds familiar, it's the active ingredient in Head and Shoulders shampoo. It's a neurotoxin if ingested.[2] No one would ever suggest pyrithione be taken internally.

The authors say zinc acetate was highly toxic to the cells at 8 μM, but inhibited RNA-synthesizing activity above 150 μM. In their experiment, they used zinc at concentrations up to 500 μM, a highly toxic level. So yes, technically that amount of zinc would prevent you from dying from the coronavirus. But not the way you probably want.

A tip-off to bad science is where they claim it worked in vivo when they only tested it in Vero-E6 cells. This suggests they're unfamiliar with the term, and there are many other weird things in the paper, like using EDTA as a zinc chelator. As the authors know, EDTA would bind up all the magnesium, which is bad.

True, zinc worked at 1 μM against the purified enzyme in the test tube, but that's a totally different system. And the claim of some anti-vaxxers that the symptoms of COVID-19 are the same as those of zinc deficiency is unconvincing.

The only paper that claims chloroquine is an ionophore for zinc was a study in PLoS One that used it at concentrations close to its LC50 to kill cancer cells by inducing lysosome-mediated apoptosis.[3] Leaving aside the dismal quality of that paper, killing cells by apoptosis is not exactly what we want. And from their paper, it's clear that chloroquine is a pretty crappy ionophore.

The trick to blocking SARS-type viruses is to find a protease inhibitor that specifically prevents cleavage of the spike protein. If the spike protein doesn't get cleaved, the virus can't enter the cell. There are some drugs out there that do this, but there's little interest because they haven't undergone clinical trials, and it's unlikely they ever will: finding sick people after the epidemic is over is a royal pain. It's also unethical to give healthy people the virus (though that hasn't stopped people from suggesting it). So when the next deadly pathogen flies out of a Chinese wet market like a bat out of hell and starts slaughtering people, we'll be back to square one. No matter: two weeks from now no one will care and everyone will go back to calling each other racists.

The coronavirus itself contains zinc binding sites[4,5] and some authors speculate that zinc is essential in maintaining the virus structural integrity. Another article[6] says while the surface protease TMPRSS2 increases cell entry, matrix metalloproteinase (MMP)- and ADAM-family zinc metallo­prot­eases are involved in both entry and cell-cell fusion. If true, both findings mean giving people zinc could well make things worse. Biology is complicated.

Another paper[7] says zinc has no viricidal effects against transmissible gastroenteritis virus, but inhibits viral penetration or egress through the membrane. And that's the key: stopping the virus from getting through the membrane is what we ought to focus on. That means going after ACE2, the receptor for SARS viruses, which by the way happens to be a zinc metalloprotease.[8] So, what happens to ACE2 if you give cells more zinc? No one knows.

ACE2 is not just found in lung, heart, and GI tract, but in many tissues[9] and anything that increases the amount of that receptor, like smoking or ACE blockers, would increase your viral load and disease severity. But again, whether that affects COVID-19 or not has to be tested and some physicians warn against changing drugs until testing is complete.

Two papers[10,11] say mercury compounds like thimerosal are good at inhibiting SARS-CoV viruses. That'll make the anti-vaxxers' heads explode. Unfortunately, there's no treatment for that.

1. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. (2010). Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 6(11), e1001176. doi: 10.1371/journal.ppat.1001176. https://www.ncbi.nlm.nih.gov/pubmed/21079686

2. Marin P, Israël M, Glowinski J, Prémont J (2000). Routes of zinc entry in mouse cortical neurons: role in zinc-induced neurotoxicity. Eur J Neurosci. 12(1), 8–18.

3. Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. (2014). Chloroquine is a zinc ionophore. PLoS One. 2014 9(10),e109180. doi: 10.1371/journal.pone.0109180. PMID: 25271834

4. Joseph JS, Saikatendu KS, Subramanian V, Neuman BW, Brooun A, Griffith M, Moy K, Yadav MK, Velasquez J, Buchmeier MJ, Stevens RC, Kuhn P (2006). Crystal structure of nonstructural protein 10 from the severe acute respiratory syndrome coronavirus reveals a novel fold with two zinc-binding motifs. J Virol. 80(16), 7894–7901. PMID: 16873246 PMCID: PMC1563791 DOI: 10.1128/JVI.00467-06

5. Clayton D, Hanchapola I, Thomas WG, Widdop RE, Smith AI, Perlmutter P, Aguilar MI (2015). Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors 1 and 2. Front Pharmacol. 6, 5. doi: 10.3389/fphar.2015.00005. eCollection 2015. pmid: 25688208 PMCID: PMC4311625 DOI: 10.3389/fphar.2015.00005

6. Phillips JM, Gallagher T, Weiss SR. (2017). Neurovirulent Murine Coronavirus JHM.SD Uses Cellular Zinc Metalloproteases for Virus Entry and Cell-Cell Fusion. J Virol. 91(8), pii: e01564-16. doi: 10.1128/JVI.01564-16. PMID: 28148786

7. Wei Z, Burwinkel M, Palissa C, Ephraim E, Schmidt MF (2012). Antiviral activity of zinc salts against transmissible gastroenteritis virus in vitro. Vet Microbiol. 160(3–4):468–472. doi: 10.1016/j.vetmic.2012.06.019.

8. Guy JL, Lambert DW, Warner FJ, Hooper NM, Turner AJ (2005). Membrane-associated zinc peptidase families: comparing ACE and ACE2. Biochim Biophys Acta. 1751(1),2-8. PMID: 16054014 PMCID: PMC7105243 DOI: 10.1016/j.bbapap.2004.10.010

9. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H (2004). Tissue distribution of ACE2 protein, the functional receptorfor SARS cornavirus. A first step in understanding SARS pathogenesis. J. Pathol. 203, 631.

10. Lee CC, Kuo CJ, Hsu MF, Liang PH, Fang JM, Shie JJ, Wang AH (2007). Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors. FEBS Lett. 581(28), 5454–5458.

11. Hsu JT, Kuo CJ, Hsieh HP, Wang YC, Huang KK, Lin CP, Huang PF, Chen X, Liang PH. (2004). Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV. FEBS Lett. 574(1–3):116–120.

apr 07 2020, 7:48 am. minor edits apr 08 2020, 3:55 am

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