key: cord-350622-8tgxdbyi authors: Palit, Partha; Chattopadhyay, Debprasad; Thomas, Sabu; Kundu, Amit; Kim, Hyung Sik; Rezaei, Nima title: Phytopharmaceuticals mediated Furin and TMPRSS2 receptor blocking: can it be a potential therapeutic option for Covid-19? date: 2020-10-28 journal: Phytomedicine DOI: 10.1016/j.phymed.2020.153396 sha: doc_id: 350622 cord_uid: 8tgxdbyi Currently, novel coronavirus disease (Covid-19) outbreak creates global panic across the continents, as people from almost all countries and territories have been affected by this highly contagious viral disease. The scenario is deteriorating due to lack of proper & specific target-oriented pharmacologically safe prophylactic agents or drugs, and or any effective vaccine. drug development is urgently required to back in the normalcy in the community and to combat this pandemic. Thus, we have proposed two novel drug targets, Furin and TMPRSS2, as Covid-19 treatment strategy. We have highlighted this target-oriented novel drug delivery strategy, based on their pathophysiological implication on SARS-CoV-2 infection, as evident from earlier SARS-CoV-1, MERS, and influenza virus infection via host cell entry, priming, fusion, and endocytosis. An earlier study suggested that Furin and TMPRSS2 knockout mice had reduced level of viral load and a lower degree of organ damage such as the lung. The present study thus highlights the promise of some selected novel and potential anti-viral Phytopharmaceutical that bind to Furin and TMPRSS2 as target. As, few of them had shown promising anti-viral response in both preclinical and clinical study with acceptable therapeutic safety-index. Hence, this strategy may limit life-threatening Covid-19 infection and its mortality rate through nano-suspension based intra-nasal or oral nebulizer spray, to treat mild to moderate SARS-COV-2 infection, when Furin and TMPRSS2 receptor may initiate to express and activate for processing the virus to cause cellular infection by replication within the host cell. The global data on severity and mortality of the coronavirus disease 2019 shows that the people of almost all countries and territories have been struggling due to lack of a specific vaccine or effective prophylactic and or drug. A commercial vaccine (live attenuated, heat-killed, RNA or subunit) for the susceptible population usually takes time. While, to date, most of the anti-viral protease inhibitors (Ritonavir, Lopinavir, Remdesivir, Hydroxychloroquine, etc.) used in Covid-19 patients is based on trial and error basis. Most cases, patients are failed to recover due to nonspecific drug binding, and adverse reaction due to patient's co-morbid conditions including organ malfunctioning (Cameron et al., 2001; Zumla et al., 2016; Lenkens et al., 2020; Carter et al., 2020; . So, drug target identification, followed by specific drug delivery for rapid healing and protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgent treatment issues. The SARS-CoV-2, the causative agent of COVID-19, is an enveloped, non-segmented positivesense single-stranded (ss) RNA virus that contains four structural proteins: Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N) proteins (De Wit et al., 2016; Drosten et al., 2003) . It is reported that the Spike glycoprotein of this virion harbors a Furin cleavage site, at the boundary between its two subunits, S1/S2, which is activated by the host cell enzyme Furin proprotein convertase to make the virus more susceptible to its primary receptor, angiotensinconverting enzyme-2(ACE2) (Walls et al., 2020) . Furin also helps the virion to bind with ACE2 efficiently, via the receptor-binding domain of S-protein, to transmit the virus as stable form and invade the host cell rapidly for further pathogenicity (Coutard et al., 2020; Walls et al., 2020) . The receptor-binding domain (RBD) of S-protein after cleavage mediating processing, followed by activation, is responsible for binding with ACE2; while the interaction of S-protein with host cell ACE2 receptor helps the virus to invade the host cell (Li et al., 2005) . The binding affinity of Sprotein of SARS-nCoV-2 with ACE2 is about ten times higher than Corona viruses including SARS-CoV-1(Lau et al., 2003; Ge et al., 2013) , indicated that CoV-2 infection depends on host cell ACE2 receptor expression. Furthermore, TMPRSS2 (Transmembrane protease serine 2) fuse and activate the S-protein-ACE2 complex into the host cell endosome, via proteolytic digestion of the S-protein's S2 domain through membrane fusion (Hoffmann et al., 2020) . This cascade helps to promote the pathogenicity and life-cycle, for which ACE2 and TMPRSS2 can be served as a viable target for nCoV-2 therapy. It has been found that Furin and TMPRSS2 could play a significant role for efficient attachment of cleaved S-protein with host cell ACE2 receptor via activation, priming, and fusion, followed by endosomal internalization to establish pathogenicity through replication, growth, and spread of the infecting virus to another organ's cell. The proteolytic activity of such transmembrane serine protease, prior to cleavage, activation and fusion have been exploited by the S-protein of Covid-19 virus towards stronger infection (Hoffmann et al., 2020) . Our current understanding will focus on the promise of suitable ligand on those drug targets, via intra-nasal or oral nano-suspension spray-based drug delivery, to tackle this pandemic panic. Earlier studies indicated that the pre-treated hypertensive patients, particularly with Angiotensin receptor-1 (AR1) blocker (Losartan or Telmisartan), may recover and help to protect from Covid-19 infection and as well as to reduce the recovery time and mortality (Rothlin et al., 2020; Magrone et al., 2020; Tomasoni et al., 2020) , because those AR1 blockers could attenuate the angiotensin-2 mediated vasoconstriction, inflammation, lung injury, lung fibrosis, and cell damage. Moreover, these drugs can counterbalance the ACE/Ang-II/AT1R axis upregulation, mediated by the renin-angiotensin-aldosterone system (RAAS), a signalling disorder in the hypertensive patient. Furthermore, those drugs may upregulate the ACE2/Ang1-7/MasR homeostatic axis for better recovery from hypertension, which is being suppressed by the Covid-19 infection due to utilization of ACE2 by the viral S-protein for virus entry. It has been reported that ATR1 receptor antagonist could reduce the virus-driven lung injury, edema, inflammation and acute lung pneumonia (Sanchis-Gomar et al., 2020; Mousavizadeh et al., 2020) . Moreover, Losartan, an angiotensin receptor blocker, has been reported as an anti-inflammatory and antifibrotic agent (Arjmand et al., 2019; Dionísio et al., 2019) , and thus could play a significant role to ameliorating the post-infective cytokine storm and organ damage. It can be hypothesized that the continuation of ARBs (Angiotensin-II receptor blockers) treatment for Covid-19 patient, may lead to early recovery. ACE2 is known to be present in the host cell membrane surface of esophagus, lungs, heart, intestine, kidney, prostrate, and brain (Sanchis-Gomar et al., 2020) . It has a functional role in facilitating SARS-CoV-2 invasion to host cells, and thus, ACE2 antagonist could be a more promising treatment option in Covid-19 patients (Kuba et al., 2006) . It will be very interesting to explore those host cell receptor blockers that could be the novel drug target for effective and safe therapeutic option to fight SARS-CoV-2 infection (Hoffmann et al., 2020; Shin et al., 2017; Gurwitz et al. 2020) . This approach can successfully prevent the attachment and pharmacodynamic interactions between host-virus to stop further infection of This cascade may also lead to prevent the entry of this deadly virus into the host cell via endocytosis, and subsequent replication of the virus, leading to stop further division, assembly and life-cycle. This therapeutic strategy could be the game-changer as a prophylactic treatment, and to attenuate the mortality as well as to cope-up with SARS-CoV-2 infection, as evident from a previous report (Ho et al., 2007) . The ACE2 receptor is located in many organs of human body, including esophagus and lung cells. The COVID-19 virus usually enters the human body through the mouth and nostrils and target the goblet and ciliated cells. Therefore, there is an ample scope for the virion to catch the first door, ACE2 receptor located in esophageal cells, followed by the lungs for entering inside the target cell to release viral-RNA in cell cytoplasm for replication. The higher binding affinity of the Covid-19 virus to the ACE2 active site compared to SARS-CoV-1 may result in greater endocytosis and translocation of both the virus-enzyme complex into the host cell endosomes (Wang et al. 2008; Millet et al., 2017; . It will be a novel approach to handle Covid-19, if any stable Phyto-lead molecule can be identified from the age-old traditional medicinal herbs and spices (Table 1) , like Emodin (Ho et al., 2007) , that could block the interaction between S-protein of Coronavirus and ACE2 receptor of the human host. However, the approach of blocking ACE2 receptor-mediated virus entry may be contraindicated for hypertensive patients, who are suffering from malfunctioning of kidney and associated RAAS disorder mediated hypertension. Angiotensin-2 receptor blocker (AT1, Losartan, telmisartan) reduces the blood pressure in hypertensive patients who are suffering from kidney disorders, via competitive inhibition of angiotensin-2 signalling molecule that binds with the AT1 receptor. If the angiotensin 2 binds with AT1 receptor in the absence of ARBs, it could lead to vasoconstriction, followed by hypertension and cardiac hypertrophy as a consequence of the release of aldosterone hormone, leading to the severe lung injury (SLI) and acute lung respiratory disorders (ALRD). These could be a fatal manifestation for Covid-19 patients' comorbidity of hypertension. On the other hand, excess angiotensin 2 converts into angiotensin-(1-7) by the ACE2 receptor, located in the lung, kidney, and esophagus cell surface. This angiotensin-(1-7) elicits hypotensive effect via vasodilation of artery and blood vessels by releasing Nitric Oxide. Meanwhile, if SARS-CoV-2 invades hypertensive host to enter the target cell via ACE2 receptor; then ACE2-induced homeostatic mechanism and normal physiological activity would be suppressed, with disruption of the production of vasodilator, angiotensin-(1-7) molecule. Therefore, the entry of Covid-19 virus may lead to the failure of the hypertensive hosts to protect themselves from lung-fibrosis and cardiac hypertension. Thus, host-virus interaction via ACE2 receptor attachment, followed by virion-induced free radical generation and inflammasome, may generate pro-inflammatory cytokine storm that affects the other organs. Patients susceptible to cardiac arrest and organ failure could lead to a fatal outcome, even death, due to this kind of abnormal cell signalling. Moreover, ACE2 has a significant role in protecting major organ failure due to hypertension and angiotensin-2 mediated lung disorders (Kuba et al., 2020) . Studies conducted in mice showed that the interaction of Coronavirus spike protein with ACE2 receptor persuades a decline in the levels of ACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage (Imai et al., 2008; Jia, 2006) . Thus, ARBs therapy could reduce the chances of pneumonia, and lung damage along with the control of hypertension, pulmonary oxygen saturation, and cardiac risk in the Covid-19 patient (Saavedra et al., 2020) . AT1 receptor antagonist treatment forces to bind the Angiotensin 2 with the AT2 receptor to prevent lung injury and damage following the hypotensive effect. A recent study illustrated that Covid-19 patients pre-treated with ARBs have significantly reduced mortality and does not require hospitalization or further intensive care (Rothlin et al., 2020; Magrone et al., 2020; Tomasoni et al., 2020) . The primary function of ACE2 is to counterbalance the ACE function to reduce blood pressure and inflammation in the body. Binding of Coronavirus S-protein with ACE2 receptor and its translocation may lead to complete loss of its hypotensive, anti-inflammatory and antioxidant property. So, S-protein binding with ACE2 receptor may augment the serious side effects, such as lung injury, fibrosis, hypertension and acute inflammation due to upregulated production of Angiotensin II in co-morbid cases. Hence, it can be postulated that ACE2 receptor blocker mediated drug therapy may not be fruitful as a prophylactic or therapeutic agent for the hypertensive patient suffering from renal dysfunction to fight Covid-19. Because, the downregulation of the ACE2 receptor may trigger similar serious side effects like lung and other organ damage, owing to angiotensin-2 mediated hypertension and pneumonia, as observed during COVID-19 infection. Nevertheless, for healthy normal people treatment with ACE2 receptor blocker could successfully counter the cellular entry of SARS-CoV-2. It is interesting to note that after the binding of novel coronavirus spike protein with ACE2 receptor, the adjacent serine protease TMPRSS-2 receptor of host cell helps to allow the virion to enter into the intracellular endosome, by priming of S-2 domain of S protein (Heurich et al., 2014) . Therefore, inhibition of TMPRSS2 by appropriate and specific phytochemicals, derived from traditional medicines like Ayurveda (Vellingiri et al., 2020) and Unani (Nikhat et al., 2020) could be the potential therapeutic intervention for the management of Covid-19. Expression of this cell surface receptor helps to augment the chance of infection by facilitating the endocytosis of SARS-CoV-2 and ACE2 complex into the host cell endosome (Matsuyama et al., 2020) . Moreover, the hypertensive patient may get better benefit with the TMPRSS2 inhibitor to fight against SARS-CoV-2 infection, and pathogenesis (Shen et al., 2017) , influenza and other coronavirus infections, due to more or less similar pathophysiological symptoms. So far, many TMPRSS2 inhibitors of plant origins are reported, and some of the most promising candidates are depicted in Table 1 as possible prevention or remedy against this horrible respiratory infection. Additionally, some of those compounds (spices derived phyto-compounds) having identified mechanism of action against SARS and RNA virus has been presented in Table 2 . Prophylactic therapy with the dual blocker of ACE2 and TMPRSS2 receptor to healthy people, without cardiac and kidney disorders may provide excellent result by blocking the virus attachment to the host cell and translocation of the virion into the intracellular endosome. Due to strong and efficient binding ability of S-protein with ACE2 receptor, particularly in lung cells, leads to lung damage with hyperactive cytokine storm mediated acute inflammation to another organ (Kuba et al., 2020) . Thus, the combinatorial therapy of anti-inflammatory agent along with TMPRSS2 receptor antagonist may hold good promise for both therapeutic as well as a prophylactic treatment to cope up with this deadly virus. Those molecules as a combination may be delivered in situ by nano-aerosol suspension inhaler via oral or intra-nasal route rapidly in target-oriented manner at the TMPRSS2 receptor-binding site of esophagus and lung thereby block the endosome internalization of the virus-ACE2 complex. This kind of therapy can be improved by the addition of competitive ACE2 receptor binding antagonist of viral Sglycoprotein. However, virtual simulation analysis revealed that this highly contagious coronavirus also invades the human body via three more cell surface receptors including (i) Glucose Regulated Protein 78 or GRP78 (Ibrahim et al., 2020) , (ii) CD26 (cluster of differentiation 26) or dipeptidyl peptidase 4 (DPP4), a key immunomodulatory player for cell hijacking and virulence (Lu et al., 2013; Vankadari et al., 2020) , and (iii) Basigin (BSG) or extracellular matrix metalloproteinase inducer (EMMPRIN) or CD147 . The binding of the SARS-CoV-2 spike protein with those three-cell surface receptor(s) has been illustrated, based on computational insilico analysis. Hence, this type of attachment needs to be validated by physical experimentation in the laboratory with the causative virus, SARS CoV-2, responsible for Covid-19. Finally, if the CD26, CD147, GRP78 receptor binding of SARS-CoV-2 is excluded due to deficiency of proper experimental validation, we may focus predominantly on the three cell surface receptors such as Furin, ACE2 and TMPRSS2 for potential therapeutic target (Shen et al., 2017) to seal the intracellular entry of the virus, as depicted in Figure 1 . However, if we discard the ACE2 receptor blocking approach due to unavoidable limitation related to kidney disorder and diabetes, then dual inhibition of TMPRSS2 and Furin protein using safe phytochemicals like Bromhexine, an inhibitor of TMPRSS2 (Maggio et al., 2020) , could be the lucrative treatment strategy for management and prevention of Covid-19. Similarly, researchers may short out several phytochemicals against host cell Furin protease for effective and safe anti-COVID-19 drug development, like Phyto-flavonoid luteolin, an inhibitor of Furin (Peng et al., 2017) . Luteolin had potent activity against wild-type and clinical isolates of HSV-2 (EC 50 22.4 and 27.5 µg/ml and EC 99 at 40.2 and 49.6 µg/ml (Ojha et al., 2015) , and replication of dengue virus via Furin proprotein convertase inhibition (Peng et al., 2017) . Additionally, luteolin possess anti-seditious (Aziz et al., 2018) and immunomodulatory activity (Hosseinzade et al., 2019) . However, the designed and predicted Phyto-compounds needs to have interacted with the host cell surface receptor with optimal inhibition, as well as constant and stable binding at pharmacological relevant concentration. These strategies could be achieved by in-silico homology modelling, molecular docking, molecular dynamics simulation, followed by the validation through in-vitro model of inhibition studies on the interaction between host cell receptor and Spike protein of novel coronavirus. Thus, our study suggests an investigation of the localization of host cell receptor and spike protein binding by ELISA, FACS, receptor binding fluorescent assay, and immuno-electron microscopy. The anti-inflammatory and immunomodulatory activity of an anti-viral agent seems to be additionally beneficial to protect the damage of organs like lungs, heart, liver and kidney from virus-driven Th1/Th2 mediated inflammatory cytokine storm during the Covid-19 (Stebbing et al., 2020; Mehta et al., 2020) . Therefore, the identification of any antivirally active Phyto-compounds having anti-inflammatory and immunomodulatory activity will be of immensely helpful to control the super-spreading Covid-19. Rationally selected host cell receptor blocker may be explored as a promising treatment option on Covid-19 patient, if the compounds additionally exhibit anti-thrombotic effect alone or in combination (Galimberti et al., 2020) . Recent reports suggest that the Covid-19 patient with acute infection may die due to blood clotting mediated pulmonary lung coagulopathy (Connors et al., 2020; Menezes-Rodrigues et al., 2020) . Moreover, this validated receptor blockers could be delivered specifically via oral or nasal spray nebulizer or vapour nano-spray formulation-based drug delivery to the corresponding host cell receptor, located at oral mucosa, nasal membrane and lung cell surface receptor membrane. This tactic could be appropriate; because of the micronized nano-aerosol suspended drug particle would bind very rapidly to the Furin and TMPRSS2 receptor(s) of the goblet and ciliated cells in upper respiratory tract in a small concentration, via targeted novel drug delivery system. Furthermore, drug formulated in e-cigarette (Breitbarth et al., 2018) could deliver the active constituent quickly into the lung cell surface receptor for competitive binding to block the virus attachment(entry) into the host cell surface. The strategy would provide promising therapeutic intervention towards the emerging insight of prophylactic treatment as supported by the earlier report on the treatment of influenza patient with intranasal or oral delivery of anti-viral drug successfully (Peng et al., 2007; Wong et al., 2010; Dickens, 2007) . The novel approach of such drug delivery may improve the pharmacokinetic behaviour of the anti-viral prophylactic or therapeutic agent(s) by enhancing absorption and cell permeability. Drug particle formulated as a harmonious combination of cocktail receptor inhibitors at optimal and pharmacologically relevant dose could block the host cell receptor Furin, and TMPRSS2 receptor located in the target organs like esophagus, lungs, as well as in colon, liver, heart, kidneys, intestine and pancreas to prevent the entry of the SARS-CoV-2. Additionally, it may diminish the toxicity of the main active ingredient, as well (Remacle et al., 2010) . Most of the current anti-viral agents are nucleic acid analogues that directly act on the virion via conventional systemic tablet, injection have poor efficacy, prone to drug-resistance (due to frequent mutation of viral RNA and spike protein) and have undesirable side effects. Thus, when it is used against Covid-19, then those directly acting drugs may enhance the adverse drug reaction due to host cell permeability issue (Lenkens et al., 2020; Saha et al., 2020; Becerra-Flores et al., 2020) . Hence, some selected lead phytopharmaceuticals can primarily be focused on anti-COVID-19 drug discovery and development as mentioned in Table 1 and Table 2 based on their anti-viral activity reported against influenza, HIV, and other RNA viruses through host cell surface receptors ACE2, Furin and TMPRSS2 blocking action. Moreover, few of them had shown promising degree of antiviral activity in both in-vitro and invivo pre-clinical animal model as well as conferred clinical efficacy against different viral infection through clinical trial as depicted in Table 3 & Table 4 . Based on the consolidated reports on the degree of anti-viral efficacy and safety profile of the known phytocompounds as potential agents against SARS, MERS, Influenza, respiratory syncytial virus (RSV) infection, Herpes simplex virus, and HIV infection, the few potential Phyto-lead compounds could be explored against SARS-COV-2 infection to manage COVID-19 patient subjected to their preclinical and clinical investigation. Because, concised anti-viral response study depicted in Table 3 and Table 4 suggest that lycorine, flavopiridol, berberine, EGCG, cannabidiol, celastrol, Baicalein, punicalagin, mangiferin, hesperitin, silymarin, curcumin could be proceeded further to highlight them as potential prophylactic or therapeutic agent against The nasal or oral suspension or vapour spray inhaler containing multi-drug combination of phytopharmaceuticals derived from herbs, spices and traditional medicaments would deliver the active ingredient(s) specifically in the host cell receptor's (Furin, TMPRSS2) active site to block the attachment of viral S-protein via hindering the S-protein cleavage activation, followed by membrane fusion. This strategy may offer a steady and putative anti-viral response, permit to use lower doses of the Phyto-drug, and minimize the side effects, as reported earlier like zinc nasal spray in upper respiratory tract illness (Belongia et al., 2001) . It may help to mediate successful anti-viral therapy against SARS-nCoV-2 in upper respiratory tract via preventive or therapeutic treatment option (Hayden et al., 2003) . Herbs containing polyherbal Phytocomponents (Table 1,2,3 &4) may act on different stages of viral infection cycle for prevention and healing, as follows: 1) May stimulate the innate immunity for killing of the virus via Tc or NK cell mediated immune-modulation due to the presence of immunogenic phytonutrients and amino acids. 2) Could interfere the interaction of the virus with the host cell entry receptors to prevent their cellular endocytosis, replication and infection. 3) Can protect the vital and target organs by executing the anti-inflammatory activity against cytokine storm induced organ damage, as anti-inflammatory activity of the natural herbs or Phytocompounds may confer the vasodilation of bronchial tube (Ignarro, 2020; Scavone et al., 2020) . Further, the intra-nasal nanosuspension based aerosol spray inhaler(nebulizer) may help to reach the active ingredient to the lungs and esophagus rapidly; so, the formulated combination of antiinflammatory, as well as host cell entry blocker, could protect the patient from virus-driven lung injury, fibrosis, and infection by local action. In this context, few anti-inflammatories as well as anti-viral Phyto-compounds derived from herbs and spices such as carnosic acid, Eugenol, Gingerol, Eucalyptol, Cinnamaldehyde, green tea and white tea essential oils ( Table 3 & 4) may be formulated as oral or nasal nebulizer for effective drug delivery of the active medicament into the lungs, or upper respiratory tract due to their protecting ability against SARS viral infection mediated Acute respiratory distress syndrome (ARDS), Acute lung inflammation (ALI), as evident from earlier patented product formulation against influenza virus infection and associated respiratory inflammation & distress(US7596836B2, patent). Some promising leads such as Tetrahydrocannabinol, Cannabidiol, Andrographolides have been recruited in the clinical trial for the intervention of cancer and inflammation for the practical use. Bromhexine has already been marketed as commercially FDA approved medicine for practical use towards the treatment of respiratory disorders as mucolytic agent. Moreover, few plant-based antiviral compounds (such as Ursolic acid, Vitexin, wogonin, Baicalein, curcumin, gingerol, carnosic acid, Gingerol, Lycorine, Ginsenoside Rg3, Hesperetin, Tetrahydrocannabinol, Cannabidiol, Resveratrol, Glycyrrhizic Acid, Epigallocatechin 3-gallate, Luteolin) also possess promising anti-oxidant, anti-inflammatory, anti-coagulant activity at various pharmacological doses. Therefore, those compounds could be the potential therapeutic option to attenuate the cytokine storm in the acute symptomatic Covid-19 patient due to their significant anti-inflammatory activity by suppressing the liberation of inflammatory cytokines during immunopathological response of host against viral infection. Anti-coagulant property of such anti-viral phyto-molecules could be used as probable management of the pulmonary coagulopathy and blood clotting in the blood vessels to decrease the mortality rate and assist for early recovery. Anti-oxidant and strong anti-inflammatory activity of those compounds could be potential for the practical use to manage vasculitis like manifestation of the recovered patients as per the current clinical reports. Furthermore, electronic metered chip device could optimize the pharmacological dose of the delivered agent to the target cell and maintain the stability of the phytopharmaceuticals by nanosuspension coating of natural polymer. Thus, it could maintain the safety, accuracy and efficacy of the formulated dose. This method would be promising and less likely to produce sideeffect and drug resistance, as suggested by the WHO for multi-drug therapy in tuberculosis or leprosy. Hence, it could be hypothesized that intra-oral or intra-nasal inhaler-based aerosol spray (Ignarro, 2020) could deliver the drug accurately to viral entry point as cell surface receptor blocker, which could be the potential, safe and rapid prophylactic as well as a therapeutic option against Covid-19 pandemic. Furthermore, the selection of the drug candidate to be delivered via nasal or oral spray formulation is very important and thus the selected pharmacological agents should possess the immunomodulatory property and block the virus entry to the host cell receptor via dual blocking of Furin protease and TMPRSS2 receptor site. For this, adaptogenic herbs from the traditional system of medicine like Ayurvedic and Unani may be useful as rational formulation. Nano-spray suspension coated with a stable polymer and suspending agents along-with receptor-ligand could stabilize the entrapped Phyto-pharmacological agents like curcumin-nano-formulation (Preis et al., 2019; Taki et al., 2016) for longer duration avoiding the pharmacokinetic failure. The application of nano-spray might be useful also to contain the infection for spreading further, when mild to moderate symptoms would arise by augmenting the cell surface receptor activation (Furin and TMPRSS2). This projected drug delivery via nasal or oral nano-spray comprising of stable Phyto-immunomodulators and entry receptor blocker can be scaled up to achieve the expected recovery and eradicate the Covid-19 pandemic and its panic, subjected to preclinical and clinical validation. The authors declare that they have no known competing financial interests or no conflict of interest Enmozhi, S.K., Raja, K., Sebastine, I., Joseph J., 2020. 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