Can concomitant use of zinc and curcumin with other immunity-boosting nutraceuticals be the arsenal against COVID-19?

Dear Editor,

The recent pandemic spread of COVID‐19 has socio‐economically crippled the world and threatened humanity akin to World War II situation. The rise of this novel strain, SARS‐CoV‐2, and its exponential transmission rate have hindered the researchers to find a plausible prophylaxis and therapy to date. Therefore, slowing down the transmission rate is the only possible action plan. Thus, WHO recommended social distancing and improving personal hygiene as a protective measure, adhering to which, nations around the globe have imposed a total lockdown for its citizens.

Aging and/or immunocompromised populations, as well as polymorbid patients, are the most vulnerable toward COVID‐19, according to mortality and morbidity reports around the globe (Koff & Williams, 2020). It suggests that the COVID‐19 has a proximate association with innate and adaptive immune responses, which declines with age and diseases. Further scientific investigations are warranted in these directions. However, the diet has an integrated role in raising our immune responses against pathogenic invasions. Adequate and proper nutrition is required for an “activated” immune system to meet the demand for energy during periods of infection. Micronutrients and dietary components play a specific role in the development and maintenance of an effective immune system, for example, Vitamin A and Zinc (Zn), via regulating cell division, which is involved in the proliferative response of the immune cells (Childs, Calder, & Miles, 2019). Whereas, Vitamin E is an antioxidant involved in the activation of protein kinase C. Similarly, prebiotic and probiotic‐rich diets enrich the gut microbiota, which further nourishes the components of the immune system, such as immunoglobulin A (IgA). The majority of such immune cells reside in gut‐associated lymphoid tissues, thus reflecting its importance in maintaining host health.

Lack of effective prophylaxis against COVID‐19 has prompted regulatory authorities to propose boosting of immunity of individuals via nutritional supplements. While modern medicine directly confronts an antigen (via vaccination or antibiotic), in comparison nutraceuticals, food supplements, and traditional medicines activate the overall immunity of the human body. To maintain optimum health during this lockdown period, recently, Ministry of AYUSH, Government of India, has also stressed upon various immunity‐boosting steps concerning Ayurveda (AYUSH, 2020). Several suggestions from daily intake of warm water, Haldi, herbal tea, etc., to practicing yoga and Pranayama, have been suggested by the Indian Government.

The hypothesis of Ayurveda or any other traditional system of medicine has been built around the concepts of practicing daily/seasonal regimes and consuming nutrients that further nourishes us and develops overall natural resistance against pathogens. US Food and Drug Administration (FDA) has already approved various food and immunity‐boosting dietary supplements as safe (GRAS) level. Reports from China validate the use of Traditional Chinese Medicine (TCM) which has found success against COVID‐19. A decoction of Qing Fei Pai Du (QPD), a TCM, has proven its effectivity in COVID‐19 patients. Out of 701 confirmed cases treated by QPD, 130 cured cases, 51 cases with disappeared clinical symptoms, 268 cases of improved symptoms, and 212 cases of stable symptoms were found without aggravation (Ren, Zhang, & Wang, 2020). Thus, we can expand our discussion by taking the example of two nutritional supplements—Curcuminoids and Zn—which have been classified under GRAS, by FDA, as nutraceutical and nutrient. Both molecules have a proven history of antiviral activity in both in vitro and in vivo trials, and thus could be leading in developing new prophylactic candidates against COVID‐19.

Curcumin is a natural bioactive polyphenolic compound isolated from the dried powder of Curcuma longa rhizomes, commonly known as turmeric (Haldi in Hindi), and widely used worldwide for cooking. Ayurveda mentioned the use of turmeric for numerous therapeutic purposes like blood coagulation to immune stimulation. An array of systemic antioxidant properties has been attributed to curcumin‐containing nutraceuticals. For example, it exerts an anti‐inflammatory action in arthritis and inflammatory bowel diseases, reduces lipid levels in cardiovascular diseases, and addresses oxidative stress in skin disorders (Pagano, Romano, Izzo, & Borrelli, 2018). Curcumin has an established track record as an antiviral agent against several viruses like Influenza Type A, Hepatitis A, Zika, HIV, etc. The mode of action of curcumin includes—inhibition of viral entry into cells, suppression of viral replication, stimulation of interferons (IFNs) and other cytokines, and inhibition of viral protein expression. In silico studies have also revealed that curcumin binds directly with the receptor‐binding domain of the viral spike protein (involved in host cell binding) and the cognate host cell receptor, angiotensin‐converting enzyme‐2 (serves as a medium of viral entry), of SARS‐CoV‐2 virus (Figure 1). Moreover, curcumin has been reported to inhibit the release and suppress numerous cytokines like IL‐1β, IL‐6, IL8, TNFα, MCP‐1, etc. When investigated in various viral infections set‐up, the mode of cytokine suppression by curcumin can be correlated with clinical improvement in conditions associated with cytokine storm (Sordillo & Helson, 2015). Following the suggested interaction with these key components of the viral lifecycle and immune system, it is apparent that curcumin could prevent the COVID‐19 infection. Moreover, in recent years, blood coagulation properties of curcumin (by inhibiting platelet aggregation, cyclooxygenase pathway, and blocking of calcium signaling) have been utilized in designing various materials and devices (Keihanian, Saeidinia, Bagheri, Johnston, & Sahebkar, 2018). As the SARS‐CoV‐2 coronavirus infection can be associated with a disseminated intravascular coagulopathy, hence curcumin can be an effective agent against this pathological condition. It should also be noted that there is the possibility that studies on curcumin have not been carried out according to more recent scientific qualitative standards for plant‐derived products (Heinrich et al., 2020). Therefore, there is the chance that high implausible concentrations in vitro or doses in vivo have been used.

FIGURE 1

Potential mechanisms by which Curcumin and Zinc can exert therapeutic effects against COVID‐19. Curcumin inhibits SARS‐CoV‐2 entry by binding directly to the receptor‐binding domain (RBD) of spike (S) protein of the virus. Whereas, Zn2+ causes inhibition of RNA‐dependent RNA‐polymerase (RdRp) and reduction in template binding [Colour figure can be viewed at wileyonlinelibrary.com]

Zn is an essential micronutrient and its deficiency influences both the natural and acquired immune system and causes oxidative stress. Physiologically, Zn is found in bound form in intracellular metallothionein proteins. Supplementation of Zn augments metallothionein expression. This leads to direct antiviral actions of metallothionein against an array of viruses by sequestering Zn away from viral metalloproteins or by acting as Zn chaperones and facilitating antiviral signaling indirectly (Read, Obeid, Ahlenstiel, & Ahlenstiel, 2019). In in vitro study, Zn was also found to interfere with the viral replication cycle by free viral inactivation, inhibiting viral uncoating, interfering with viral genome transcription, protein translation, and polyprotein processing. These antiviral properties of zinc need further validation in a clinical setup. In elderly patients, zinc deficiency is concomitant with susceptibility to infections. On supplementation of zinc, a significant drop in infection rate was observed in patients of 55–87 years along with low production of tumor necrosis factor and oxidative stress markers, further establishing the association of zinc deficiency and cell‐mediated immune dysfunction (Prasad et al., 2007). Zn supplementation can also make a positive contribution to chloroquine and other antiviral treatments applied today. Zn2+along with Zn ionophores is found to limit the replication of SARS‐CoV, by blocking RNA synthesis via inhibiting RNA‐dependent RNA‐polymerase (RdRp) (Figure 1). Consequently, Zn supplementation directed in a proper strategy can significantly protect against both chronic and acute viral infections.

One of the feasible strategies by antiviral therapeutics is to target pathways/viral mechanisms that are shared among multiple viral species (for example, cellular entry or RNA genome replication). A recent study revealed the phylogenetic resemblance of surface spike glycoprotein between SARS‐CoV‐2 and SARS‐CoV, which raises the possibility of the existence of cross‐reactive epitopes (Yuan et al., 2020). The availability of such conserved domains may serve not only as a lead toward the development of SARS‐CoV‐2 vaccine, but also for cross‐protective antibody responses against future coronavirus epidemics. Similar therapeutic approaches could be hypothesized by fusing the broad‐spectrum antiviral properties of curcumin (e.g., inhibition of viral entry) with Zn (e.g., RNA polymerase inhibition). Zn in combination with polyphenols, like curcumin, may form an ionophore complex and results in a concerted antiviral action. Thus, these supplements as a part of the food, nutraceutical, or traditional medicines may pave the way toward developing a therapeutic strategy against the COVID‐19 pandemic.

In conclusion, the novel coronavirus infection has brought the concept of boosting individual immunity at the forefront. Unless until a vaccine is discovered and “herd immunity” is brought upon masses, social isolation is the only resort to remain uninfected. The success story of TCM is continuously inspiring us to test food supplements and raise individual immunity. Can we fit curcumin and zinc into this continuing puzzle?

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHORS' CONTRIBUTION

Anupam Roy, Amit Kumar Mandal, Ismail Ocsoy: Conceptualisation, Writing—Original draft preparation. Biswatrish Sarkar, CaglaCelik, Animesh Ghosh, UtpalBasu, Malabendu Jana, Arundhati Jana, AyseGencay, Gulten Can Sezgin, NilayIldiz, Paulami Dam: Contributed as advisors during the original draft preparation and corrections for the manuscript. All authors have read the manuscript and agree with authorship.