Does zinc supplementation enhance the clinical efficacy of chloroquine/ hydroxychloroquine to win today's battle against COVID-19?
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.
Conflict of interest The author Roland Derwand is/was at the time of writing an employee of Alexion Pharma Germany GmbH. The author Martin Scholz is/was at the time of writing External Senior Advisor for the company LEUKOCARE in Munich, Germany. The authors confirm that this article content has no conflict of interest.
Anderson, Roussel, Zouari, Mahjoub, Matheau et al., Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus, J Am Coll Nutr
Braun, Rosenfeldt, Pharmaco-nutrient interactions -a systematic review of zinc and antihypertensive therapy, Int J Clin Pract
Cao, Wang, Wen, A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19, N Engl J Med, doi:10.1056/NEJMoa2001282
Cui-Cui, Rw, Repurposing host-based therapeutics to control coronavirus and influenza virus, Drug Discovery Today
Ervin, Kennedy-Stephenson, Mineral intakes of elderly adult supplement and non-supplement users in the third national health and nutrition examination survey, J Nutr
Gao, Tian, Yang, Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents, doi:10.1016/j.ijantimicag.2020.105949
Kaushik, Subramani, Anang, Zinc salts block hepatitis E virus replication by inhibiting the activity of viral RNA-dependent RNA polymerase, J Virol, doi:10.1128/JVI.00754-17
Kupferschmidt, Cohen, WHO launches global megatrial of the four most promising coronavirus treatments, Science
Prasad, Beck, Bao, Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress, Am J Clin Nutr
Rolain, Colson, Raoult, Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century, Int J Antimicrob Agents
Smith, Bushek, Prosser, COVID-19 drug therapy potential options
Velthuis, Van Den Worm, She, Sims, 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, doi:10.1371/journal.ppat.1001176
Yang, Shen, Targeting the endocytic pathway and autophagy process as a novel therapeutic strategy in COVID-19, Int J Biol Sci, doi:10.7150/ijbs.45498
Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet