Preprint Hypothesis Version 1 Preserved in Portico This version is not peer-reviewed

Does Zinc Supplementation Enhance the Clinical Efficacy of Chloroquine/Hydroxychloroquine to Win Todays Battle Against COVID-19?

Version 1 : Received: 6 April 2020 / Approved: 8 April 2020 / Online: 8 April 2020 (10:54:33 CEST)

A peer-reviewed article of this Preprint also exists.


Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.


COVID-19; SARS-CoV-2; Therapy; Chloroquine; Hydroxychloroquine; Zinc


Medicine and Pharmacology, Epidemiology and Infectious Diseases

Comments (6)

Comment 1
Received: 9 April 2020
Commenter: Gerard Abate
The commenter has declared there is no conflict of interests.
Comment: The concept of utlizing zinc supplimentation for antiviral activity isn't new, but in this time of COVID19, I think it is important to test the hypothesis does zinc supplimentation as an arm to other antiviral therapies, affect concentration of viral load and duration.
Of interest would be oral zinc given in combination with hydroxychloroquine for those testing positive, given as soon as a positive test is identified to look at duration of viral activity and symptoms.
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Comment 2
Received: 13 April 2020
Commenter: Takuya Matsuda
The commenter has declared there is no conflict of interests.
Comment: Dear Sir
The idea of the use of zinc and Chloroquine/Hydroxychloroquine was presented by Dr. Seheult in the YouTube channel PubMed as follows:

Coronavirus Epidemic Update 34: US Cases Surge, Chloroquine & Zinc Treatment Combo, Italy Lockdown
A possible mechanism is also discussed. The point is that Chloroquine/Hydroxychloroquine works as a zinc ionophore.

In another video he discusses other possible ionophores, quercetin and epigallocatechin-gallate. Therefore, it is interesting to see the effect of the dose of both zinc and quercetin/epigallocatechin-gallate.

Coronavirus Pandemic Update 35: New Outbreaks & Travel Restrictions, Possible COVID-19 Treatments
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Comment 3
Received: 18 April 2020
The commenter has declared there is no conflict of interests.
Comment: J Xue has already completed such a study for NIH in 2014....exactly why is this debate raging on?
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Response 1 to Comment 3
Received: 20 April 2020
The commenter has declared there is no conflict of interests.
Comment: Thank you for your comment:
If you refer to the following publication
"Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding W-Q (2014) Chloroquine Is a Zinc Ionophore. PLoS ONE 9(10): e109180." which was supported in part by the NIH, please, be aware that this work was done in vitro. The results shown in this publication of Xue J et al. provide pretty much evidence for the combined use of chloroquine/hydroxychloroquine in COVID-19 treatment strategies. However, to our knowledge, no controlled clinical study with chloroquine/hydroxychloroquine combined with zinc supplementation has been published in the context of COVID-19 therapy. If you should have further information in this regard, please provide the respective publication as a comment to this preprint publication.
Thank you for your feedback and support!
Comment 4
Received: 22 April 2020
The commenter has declared there is no conflict of interests.
Comment: The authors are correct - there are now 3 registered clinical trials which involve both CQ/HCQ and Zn(II) - two of them look at prevention, and one - at treatment. Results will be available in 24 weeks.
To the best of my knowledge, there is no literature data which links the two with Covid-19 - the paper you mention by Xue et at. is the base of the theory, yes, but it shows exactly what it says in the title (Chloroquine Is a Zinc Ionophore) and does not link CQ to any viral infection.
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Comment 5
Received: 26 April 2020
Commenter: Veronica Riveros Cuadra
The commenter has declared there is no conflict of interests.
Comment: I am an Internist, Chilean Diabetologist. I think that the entrance route of Zinc could be using the Potassium channels. As a Diabetologist, I am very struck that, like Glibenclamide, hydroxychloroquine produces Hypokalemia and Hypoglycemia
I hope to be useful.
I congratulate you for your wonderful work that contributes to a better understanding of the treatment
Dr. Veronica Riveros C
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Comment 6
Received: 26 April 2020
Commenter: Paul Schmehl
The commenter has declared there is no conflict of interests.
Comment: As far as I know, there have been no clinical trials of this combination. There are three studies on that use this protocol; one in Turkey and two in California. However, the California trials aren't even enrolling yet and won't be completed for more than a year.

The Turkish trial includes Vitamin C and D as well as Zinc in combination with HCQ as a prophylactic for healthcare workers
The two California studies will look at both prophylaxis and treatment for infected patients.

Out of the 133 studies looking at the use of HCQ either as a prophylactic or a treatment regimen, these are the only three that include zinc. It's astounding to me that the medical research community is completely ignoring this treatment, and I greatly appreciate your proposal to include it in clinical trials. The in vitro evidence suggests the combination would be effective against COVID-19 (and possibly other coronavirus infections).
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