Potential molecular mechanisms of zinc- and copper-mediated antiviral activity on COVID-19

Abstract

Novel coronavirus disease 2019 (COVID-19) has spread across the globe; and surprisingly, no potentially protective or therapeutic antiviral molecules are available to treat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, zinc (Zn) and copper (Cu) have been shown to exert protective effects due to their antioxidant, anti-inflammatory, and antiviral properties. Therefore, it is hypothesized that supplementation with Zn and Cu alone or as an adjuvant may be beneficial with promising efficacy and a favorable safety profile to mitigate symptoms, as well as halt progression of the severe form of SARS-CoV-2 infection. The objective of this review is to discuss the proposed underlying molecular mechanisms and their implications for combating SARS-CoV-2 infection in response to Zn and Cu administration. Several clinical trials have also included the use of Zn as an adjuvant therapy with dietary regimens/antiviral drugs against COVID-19 infection. Overall, this review summarizes that nutritional intervention with Zn and Cu may offer an alternative treatment strategy by eliciting their virucidal effects through several fundamental molecular cascades, such as, modulation of immune responses, redox signaling, autophagy, and obstruction of viral entry and genome replication during SARS-CoV-2 infection.

Keywords: Copper (Cu); Coronavirus disease 2019 (COVID-19); Gastrointestinal system; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Trace elements; Zinc (Zn).

Fig. 1

Implications of SARS-CoV-2 virus in intestinal cells. (a) Normal enterocyte: Zn and Cu homeostasis in healthy enterocytes is maintained through their respective transporters such as ZIP4, ZnT1, CTR1, and ATP7A. (b) SARS-CoV-2 infected enterocyte: SARS-CoV-2 infection can cause subsequent damage of intestinal enterocytes with malabsorptions of micronutrients including Zn and Cu which further aggravate viral toxicity.

Fig. 2

Zinc-mediated immunomodulatory responses during viral infection. Zn modulates both innate and adaptive response systems by regulating functional aspects of their immune cells such as macrophages, neutrophils, NK cells, T and B cells which eventually favors the establishment of antiviral states to perturb viral infection.

Fig. 3

The underlying molecular mechanism of defense against SARS-CoV-2 infection by Zn in the respiratory epithelium. SARS-CoV-2 binds to ACE2 receptors on the respiratory epithelium and leads to activation of the inducible transcription factor, NF-κB. Subsequently, it induces the expression of various proinflammatory genes and results in the production of a “cytokine storm” which further damages airways cells and eventually provokes alveolar edema and ARDS. On the other hand, Zn may target multiple pathways to hamper the functional and structural consequences of inflammatory response caused by SARS-CoV-2.

Fig. 4

The detailed molecular mechanism followed by Cu in the respiratory epithelium to escape from COVID-19 infection. The cellular entry of SARS-CoV-2 virus induces NF-κB, an inducible transcription factor which is responsible for inflammation by stimulating the proinflammatory genes. Conversely, Cu may prompt a number of mechanistic cascades to obstruct SARS-CoV-2-induced inflammatory events.