key: cord-350697-u032yk0z authors: Roy, Anupam; Sarkar, Biswatrish; Celik, Cagla; Ghosh, Animesh; Basu, Utpal; Jana, Malabendu; Jana, Arundhati; Gencay, Ayse; Sezgin, Gulten Can; Ildiz, Nilay; Dam, Paulami; Mandal, Amit K.; Ocsoy, Ismail title: Can concomitant use of zinc and curcumin with other immunity‐boosting nutraceuticals be the arsenal against COVID‐19? date: 2020-06-02 journal: Phytother Res DOI: 10.1002/ptr.6766 sha: doc_id: 350697 cord_uid: u032yk0z nan 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). Several suggestions from daily intake of warm water, Haldi, herbal tea etc., to practicing yoga and Pranayam, 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 which 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 et al., 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 thus could be leadings in developing new prophylactic candidates against COVID-19. This article is protected by copyright. All rights reserved. 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 address oxidative stress in skins disorders (Pagano, Romano, Izzo et al., 2018) . Curcumin has an established track record as an antiviral agent against several viruses 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. 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 et al., 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 tumour 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. Zn 2+ along with Zn ionophores found to limit the replication of SARS-CoV, by blocking RNA synthesis via inhibiting RNA-dependent RNA-polymerase (RdRp) (Fig. 1) Accepted Article This article is protected by copyright. All rights reserved. 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 crossreactive epitopes (Yuan et al., 2020) . The availability of such conserved domains may serve not only as a lead towards the development of SARS-CoV-2 vaccine, but also for cross-protective antibody responses against future corona virus epidemics. Similar therapeutic approaches could be hypothesized by fusing 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 ionophore complex and result in a concerted antiviral action. Thus, these supplements as a part of the food, nutraceutical, or traditional medicines may pave the way towards 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? Diet and Immune Function Best practice in research-overcoming common challenges in phytopharmacological research Curcumin, hemostasis, thrombosis, and coagulation Covid-19 and immunity in aging populations-a new research agenda The clinical efficacy of curcumincontaining nutraceuticals: An overview of systematic reviews Zinc supplementation decreases incidence of infections in the elderly: effect of 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 receptorbinding domain (RBD) of Spike (S) protein of the virus. Whereas, Zn 2+ causes inhibition of RNA-dependent RNA-polymersase (RdRp) and reduction in template binding This article is protected by copyright. All rights reserved.