**4. An array of symptoms and complications**

In general, COVID-19 infection is associated with the increased production of pro-inflammatory cytokines, C-reactive protein, increased risk of pneumonia, sepsis, acute respiratory distress syndrome, and heart failure [24]. In fact, a cluster of unexplained pneumonia cases were first reported in Wuhan, China in late December 2019. A few days later, the cause of this pneumonia was identified as a new member of the coronavirus family. Since then, the virus has spread throughout China and precipitated a global pandemic [6].

Early reports from China suggested the most common symptoms of COVID-19 infection were fever (88%) and dry cough (67.7%). Rhinorrhea (4.9%) and gastrointestinal symptoms (diarrhea 4–14%) were less common. At the same time, a majority of patients (81%) had only mild symptoms (no pneumonia or mild pneumonia). Among patients with more pronounced symptoms, 14% experienced severe symptoms while 5% were critically ill with respiratory failure, septic shock, or multiorgan dysfunction or failure [3].

Although the novel coronavirus preferentially infects cells in the respiratory tract, autopsy results from Germany showed that it can be detected in multiple organs. The highest levels of the virus were detected in the lungs and the respiratory tract, while lower levels were usually present in the heart, liver, brain, kidneys, and spleen. This data suggests that SARS-CoV-2 may spread via the bloodstream and infect other organs. It also appears that COVID-19 may predispose patients to venous thromboembolism in several different ways including via endothelial dysfunction and promotion of a procoagulatory state by tissue factor pathway activation. High plasma levels of proinflammatory cytokines were observed in a small subset of patients with severe COVID-19 and, therefore, direct activation of the coagulation cascade by a cytokine storm is also plausible [12].

In one study, it was found that 22% of critically ill patients experienced myocardial injury from the infection [3]. In another study, the incidence of thrombotic

**15**

strike a cautionary note.

*Assembling an Anti-COVID-19 Artillery in the Battle against the New Coronavirus*

complications in ICU patients with COVID-19 infections was reported to be 31%. It was concluded that COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilization, and diffuse

In addition, the COVID-19 pandemic is surprisingly associated with neurological symptoms and complications including anosmia, hypogeusia, seizures, and stroke. Although statistics are not widely available at this point, the clinical course of COVID-19 is most severe in elderly male patients with comorbidities such as hypertension, diabetes, heart disease, and obesity which are all risk factors for stroke. There appears to be hypercoagulability associated with COVID-19 as a result of a "sepsis-induced coagulopathy" that may be a predisposing factor due to the formation of blood clots in the body [28]. COVID-19 complications in the brain can include delirium, inflammation, and encephalitis. A new study from UCL suggests that serious problems can occur even in individuals with mild cases of the

A temporary loss of smell (anosmia) can be a consistent indicator of COVID-19 infection. An interesting finding is that the virus seems to change the sense of smell in patients by infecting and affecting the function of non-neural cells that support olfactory neurons. However, the neurons themselves do not appear to be infected as

Diabetes is already known to be a risk factor for COVID-19 and diabetics are more likely to die from the disease. Now, mounting evidence suggests that not only does diabetes make patients more vulnerable to the novel coronavirus, but the virus may actually trigger diabetes in some. Preliminary tissue studies indicate that the virus may act by damaging insulin-producing cells in the pancreas of affected

Even though, initially, children were thought to be unaffected by the novel coronavirus, a cluster of children with hyperinflammatory shock and features similar to Kawasaki disease and toxic shock syndrome was first reported in England. This hyperinflammatory condition could lead to severe illness, multiorgan failure, and even death in extreme cases. New reports out of the UK and US suggest that symptoms in young children (mainly toddler to elementary school age) can include inflammation of the blood vessels and coronary arteries. Almost all these pediatric cases had positive SARS-CoV-2 test results. As a result, this illness has been termed

Historically, there is no doubt that vaccines have provided a tremendous tool against infection for a variety of microbes including those causing small pox, tetanus, typhoid, cholera, and polio. Vaccines are an effective way for a population to achieve herd immunity (the concept that a pandemic will end once 60–70% of people become immune to any particular virus or microorganism). However, more recently, there are instances in which the production of viral vaccines has not been so successful as in the case of human immunodeficiency virus (HIV) and human coronaviruses (HCoVs) possibly due to their complex genomes. Virologists and immunologists maintain that it takes up to ten years to prepare a really good vaccine that has been properly tested. In fact, some of these specialists are skeptical about the race to find the first vaccine for the novel coronavirus within one year and often

There are a number of things to consider in connection with a SARS-CoV-2 vaccine. Firstly, even if a safe and effective vaccine is made against the novel

COVID-19-associated multisystem inflammatory syndrome [32].

*DOI: http://dx.doi.org/10.5772/intechopen.95100*

they do not express ACE-2 receptors [30].

**5. The scope of coronavirus vaccines**

intravascular coagulation [27].

virus [29].

individuals [31].

complications in ICU patients with COVID-19 infections was reported to be 31%. It was concluded that COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilization, and diffuse intravascular coagulation [27].

In addition, the COVID-19 pandemic is surprisingly associated with neurological symptoms and complications including anosmia, hypogeusia, seizures, and stroke. Although statistics are not widely available at this point, the clinical course of COVID-19 is most severe in elderly male patients with comorbidities such as hypertension, diabetes, heart disease, and obesity which are all risk factors for stroke. There appears to be hypercoagulability associated with COVID-19 as a result of a "sepsis-induced coagulopathy" that may be a predisposing factor due to the formation of blood clots in the body [28]. COVID-19 complications in the brain can include delirium, inflammation, and encephalitis. A new study from UCL suggests that serious problems can occur even in individuals with mild cases of the virus [29].

A temporary loss of smell (anosmia) can be a consistent indicator of COVID-19 infection. An interesting finding is that the virus seems to change the sense of smell in patients by infecting and affecting the function of non-neural cells that support olfactory neurons. However, the neurons themselves do not appear to be infected as they do not express ACE-2 receptors [30].

Diabetes is already known to be a risk factor for COVID-19 and diabetics are more likely to die from the disease. Now, mounting evidence suggests that not only does diabetes make patients more vulnerable to the novel coronavirus, but the virus may actually trigger diabetes in some. Preliminary tissue studies indicate that the virus may act by damaging insulin-producing cells in the pancreas of affected individuals [31].

Even though, initially, children were thought to be unaffected by the novel coronavirus, a cluster of children with hyperinflammatory shock and features similar to Kawasaki disease and toxic shock syndrome was first reported in England. This hyperinflammatory condition could lead to severe illness, multiorgan failure, and even death in extreme cases. New reports out of the UK and US suggest that symptoms in young children (mainly toddler to elementary school age) can include inflammation of the blood vessels and coronary arteries. Almost all these pediatric cases had positive SARS-CoV-2 test results. As a result, this illness has been termed COVID-19-associated multisystem inflammatory syndrome [32].

### **5. The scope of coronavirus vaccines**

Historically, there is no doubt that vaccines have provided a tremendous tool against infection for a variety of microbes including those causing small pox, tetanus, typhoid, cholera, and polio. Vaccines are an effective way for a population to achieve herd immunity (the concept that a pandemic will end once 60–70% of people become immune to any particular virus or microorganism). However, more recently, there are instances in which the production of viral vaccines has not been so successful as in the case of human immunodeficiency virus (HIV) and human coronaviruses (HCoVs) possibly due to their complex genomes. Virologists and immunologists maintain that it takes up to ten years to prepare a really good vaccine that has been properly tested. In fact, some of these specialists are skeptical about the race to find the first vaccine for the novel coronavirus within one year and often strike a cautionary note.

There are a number of things to consider in connection with a SARS-CoV-2 vaccine. Firstly, even if a safe and effective vaccine is made against the novel

*Some RNA Viruses*

**View of Mumbai Harbour – December 2019**

In general, COVID-19 infection is associated with the increased production of pro-inflammatory cytokines, C-reactive protein, increased risk of pneumonia, sepsis, acute respiratory distress syndrome, and heart failure [24]. In fact, a cluster of unexplained pneumonia cases were first reported in Wuhan, China in late December 2019. A few days later, the cause of this pneumonia was identified as a new member of the coronavirus family. Since then, the virus has spread throughout

Early reports from China suggested the most common symptoms of COVID-19 infection were fever (88%) and dry cough (67.7%). Rhinorrhea (4.9%) and gastrointestinal symptoms (diarrhea 4–14%) were less common. At the same time, a majority of patients (81%) had only mild symptoms (no pneumonia or mild pneumonia). Among patients with more pronounced symptoms, 14% experienced severe symptoms while 5% were critically ill with respiratory failure, septic shock,

Although the novel coronavirus preferentially infects cells in the respiratory tract, autopsy results from Germany showed that it can be detected in multiple organs. The highest levels of the virus were detected in the lungs and the respiratory tract, while lower levels were usually present in the heart, liver, brain, kidneys, and spleen. This data suggests that SARS-CoV-2 may spread via the bloodstream and infect other organs. It also appears that COVID-19 may predispose patients to venous thromboembolism in several different ways including via endothelial dysfunction and promotion of a procoagulatory state by tissue factor pathway activation. High plasma levels of proinflammatory cytokines were observed in a small subset of patients with severe COVID-19 and, therefore, direct activation of

In one study, it was found that 22% of critically ill patients experienced myocardial injury from the infection [3]. In another study, the incidence of thrombotic

the coagulation cascade by a cytokine storm is also plausible [12].

**4. An array of symptoms and complications**

China and precipitated a global pandemic [6].

or multiorgan dysfunction or failure [3].

**14**

coronavirus, it may not be widely available in time to make a significant difference to the pandemic. Secondly, no successful vaccine against *any* coronavirus has been produced so far despite seventeen years of research. Moreover in March, the British Society for Immunology published an open letter stating that it is unknown whether this virus will induce long-term immunity in affected individuals as other related viruses do not [33]. Thirdly, certain vaccines can protect against a disease, but not against infection, so vaccinated individuals could potentially become asymptomatic carriers of SARS-CoV-2. Fourthly, some vaccines developed against SARS-CoV-1 (a close viral relative of SARS-CoV-2) actually exacerbated the disease in mice. Fifthly, although the easiest way to make a vaccine is to inactivate the pathogen, there are new vaccines in current trials based on RNA from coronaviruses or other RNA viruses that have never before been approved or tested in humans. Therefore, there could conceivably be unintended or irreversible consequences. Finally, at least one of the novel coronavirus vaccines approved for clinical trials so far has caused severe adverse events in three of eight healthy, young individuals that were tested [34] and other trials have been suspended. Unfortunately, the contamination of vaccines which are mass produced for a burgeoning human population also seems to be a potential problem and an ideal tool for rival countries to conduct biological warfare upon each other. Oral or nasal vaccines may be safer in this respect [35]. In addition, there is a physical limit to the number of vaccines a person can safely receive as new and deadlier viruses arise in the environment.

### **6. Biochemical effects of special supplements**

#### **6.1 Vitamin D**

The action of UVB radiation striking and reacting thermally with 7-dehydrocholesterol in human skin results in the production of Vitamin D3 in the human body. This form of Vitamin D is converted to the hormonal metabolite, calcitriol, in a set of biochemical reactions in the liver, kidneys, and other organs as required. Then, calcitriol binds with the nuclear vitamin D receptor, which is a DNA binding protein, that interacts directly with regulatory sequences near target genes and affects their transcriptional output.

Vitamin D also enhances cellular innate immunity partly through the induction of antimicrobial peptides, including human cathelicidin, and, defensins. Cathelicidins exhibit direct antimicrobial activities against a spectrum of microbes including many types of bacteria, enveloped and nonenveloped viruses, and fungi. The main action of these host-derived peptides is to kill the invading pathogens by perturbing their cell membranes. Moreover, vitamin D is effective in reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs leading to pneumonia during viral infections like COVID-19 and increasing concentrations of anti-inflammatory cytokines [24].

According to a recent clinical study with a large sample size taken from different countries around the world, vitamin D supplements were found to protect against respiratory tract infections including colds and influenza. The most benefit was observed in patients who were very vitamin D deficient. This protective effect is likely provided by the capacity of vitamin D to boost levels of antimicrobial peptides in the lungs [36].

Vitamin D deficiency is a world-wide problem, but is particularly pronounced in the elderly, who are at greatest risk of contracting severe COVID-19 infection. The release of pro-inflammatory cytokines is one of the major causative factors in serious COVID-19 infections. However, vitamin D modulates their presence in the

**17**

*Assembling an Anti-COVID-19 Artillery in the Battle against the New Coronavirus*

body by preventing macrophages from releasing too many inflammatory cytokines and chemokines. Calcitriol has also been found to exert an influence on ACE-2 receptors. Thus, it is not surprising that vitamin D deficiency has been correlated with COVID-19 cases and an increased risk of mortality in a European study [37].

RNA synthesis occurs in the life cycle of the SARS-CoV-1 virus in order to reproduce its genetic material and is catalyzed by an RNA-dependent RNA polymerase, which is the core enzyme of a multiprotein replication/transcription complex. In the case of SARS-CoV-1, an excess of intracellular zinc ions has been found to efficiently inhibit the RNA-synthesizing activity of this replication and transcription multiprotein. Enzymatic studies *in vitro* have revealed that zinc directly blocks the activity of the RNA polymerase by inhibiting elongation and reducing template binding. This RNA polymerase core, which is a central component of the coronaviral replication/transcription machinery, is well conserved among the members of the coronavirus family including SARS-CoV-2 [38, 39]. Therefore, it is quite possible that zinc treatment would have a similar biochemical effect on SARS-CoV-2

Since current research indicates that the mineral, zinc, can inhibit the replication of coronavirus and a variety of other RNA viruses in cell culture, it has become a potentially important and interesting supplement to study at this time. In the human body, zinc performs a variety of vital antioxidant functions and is required for maintaining good health. Inside the cell, the harmful effects of free radicals are balanced by the action of antioxidant enzymes (such as copper-zinc superoxide dismutase) and non-enzymatic antioxidants (such as metallothioneins). As zinc cannot pass easily through membranes, zinc-transporting proteins, ZIPs (Zrt-Irtlike protein or Zinc Iron permease) and ZnTs (Zinc transporters) help to facilitate this process. Metallothionein also aids in the regulation of zinc levels and the distribution of this metal in the extracellular space. The presence of zinc within the cell causes an increase in metallothionein, which is the major zinc-binding protein, and together they form a thermodynamically stable complex [40, 41]. Thus, low risk ways of increasing zinc bioavailability in the body can be safely considered.

In rats, rice fortified with zinc oxide or zinc carbonate is a feasible vehicle for zinc absorption, although zinc oxide displays lower bioavailability than zinc carbonate [42]. In young adults, zinc absorption from supplemental zinc citrate is comparable with that from zinc gluconate, but higher than from zinc oxide [43]. It is already known that zinc can be absorbed from topical (non-nano) zinc oxide by human skin in small quantities (nano forms of zinc oxide are not associated with significant zinc absorption) [44]. One of our recent studies suggests that zinc is absorbed by the human body from our suncare products (all with the same basic formula containing a medicinal form of zinc oxide) in sufficiently large quantities with regular use [45]. So, recently, when our company received an inquiry from Health Canada regarding any innovations that may benefit Canadian health workers at this critical time during the novel coronavirus pandemic, the answer was that we do have a product that may be useful to medical professionals and health workers in the field. It is a natural, award-winning suncare product specially formulated to block apoptotic sunburn (Skin Protector Plus). Its active ingredient is a non-nano, medicinal form of zinc oxide. The novel thing about this product is that it appears to be an efficient delivery system for boosting zinc levels in the whole body in a relatively short period of time. There is no toxicity associated with this product due to the use of high grade zinc oxide and natural ingredients. Since it is so safe and contains no harsh chemicals (already tested on human volunteers), no pre-clinical trials would be required to test

*DOI: http://dx.doi.org/10.5772/intechopen.95100*

and interfere with its ability to replicate.

**6.2 Zinc**

body by preventing macrophages from releasing too many inflammatory cytokines and chemokines. Calcitriol has also been found to exert an influence on ACE-2 receptors. Thus, it is not surprising that vitamin D deficiency has been correlated with COVID-19 cases and an increased risk of mortality in a European study [37].

### **6.2 Zinc**

*Some RNA Viruses*

**6.1 Vitamin D**

coronavirus, it may not be widely available in time to make a significant difference to the pandemic. Secondly, no successful vaccine against *any* coronavirus has been produced so far despite seventeen years of research. Moreover in March, the British Society for Immunology published an open letter stating that it is unknown whether this virus will induce long-term immunity in affected individuals as other related viruses do not [33]. Thirdly, certain vaccines can protect against a disease, but not against infection, so vaccinated individuals could potentially become asymptomatic carriers of SARS-CoV-2. Fourthly, some vaccines developed against SARS-CoV-1 (a close viral relative of SARS-CoV-2) actually exacerbated the disease in mice. Fifthly, although the easiest way to make a vaccine is to inactivate the pathogen, there are new vaccines in current trials based on RNA from coronaviruses or other RNA viruses that have never before been approved or tested in humans. Therefore, there could conceivably be unintended or irreversible consequences. Finally, at least one of the novel coronavirus vaccines approved for clinical trials so far has caused severe adverse events in three of eight healthy, young individuals that were tested [34] and other trials have been suspended. Unfortunately, the contamination of vaccines which are mass produced for a burgeoning human population also seems to be a potential problem and an ideal tool for rival countries to conduct biological warfare upon each other. Oral or nasal vaccines may be safer in this respect [35]. In addition, there is a physical limit to the number of vaccines a person can safely

receive as new and deadlier viruses arise in the environment.

The action of UVB radiation striking and reacting thermally with 7-dehydrocholesterol in human skin results in the production of Vitamin D3 in the human body. This form of Vitamin D is converted to the hormonal metabolite, calcitriol, in a set of biochemical reactions in the liver, kidneys, and other organs as required. Then, calcitriol binds with the nuclear vitamin D receptor, which is a DNA binding protein, that interacts directly with regulatory sequences near target genes and

Vitamin D also enhances cellular innate immunity partly through the induction of antimicrobial peptides, including human cathelicidin, and, defensins. Cathelicidins exhibit direct antimicrobial activities against a spectrum of microbes including many types of bacteria, enveloped and nonenveloped viruses, and fungi. The main action of these host-derived peptides is to kill the invading pathogens by perturbing their cell membranes. Moreover, vitamin D is effective in reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs leading to pneumonia during viral infections like COVID-19 and increasing concentrations of anti-inflammatory cytokines [24].

According to a recent clinical study with a large sample size taken from different countries around the world, vitamin D supplements were found to protect against respiratory tract infections including colds and influenza. The most benefit was observed in patients who were very vitamin D deficient. This protective effect is likely provided by the capacity of vitamin D to boost levels of antimicrobial pep-

Vitamin D deficiency is a world-wide problem, but is particularly pronounced in the elderly, who are at greatest risk of contracting severe COVID-19 infection. The release of pro-inflammatory cytokines is one of the major causative factors in serious COVID-19 infections. However, vitamin D modulates their presence in the

**6. Biochemical effects of special supplements**

affects their transcriptional output.

**16**

tides in the lungs [36].

RNA synthesis occurs in the life cycle of the SARS-CoV-1 virus in order to reproduce its genetic material and is catalyzed by an RNA-dependent RNA polymerase, which is the core enzyme of a multiprotein replication/transcription complex. In the case of SARS-CoV-1, an excess of intracellular zinc ions has been found to efficiently inhibit the RNA-synthesizing activity of this replication and transcription multiprotein. Enzymatic studies *in vitro* have revealed that zinc directly blocks the activity of the RNA polymerase by inhibiting elongation and reducing template binding. This RNA polymerase core, which is a central component of the coronaviral replication/transcription machinery, is well conserved among the members of the coronavirus family including SARS-CoV-2 [38, 39]. Therefore, it is quite possible that zinc treatment would have a similar biochemical effect on SARS-CoV-2 and interfere with its ability to replicate.

Since current research indicates that the mineral, zinc, can inhibit the replication of coronavirus and a variety of other RNA viruses in cell culture, it has become a potentially important and interesting supplement to study at this time. In the human body, zinc performs a variety of vital antioxidant functions and is required for maintaining good health. Inside the cell, the harmful effects of free radicals are balanced by the action of antioxidant enzymes (such as copper-zinc superoxide dismutase) and non-enzymatic antioxidants (such as metallothioneins). As zinc cannot pass easily through membranes, zinc-transporting proteins, ZIPs (Zrt-Irtlike protein or Zinc Iron permease) and ZnTs (Zinc transporters) help to facilitate this process. Metallothionein also aids in the regulation of zinc levels and the distribution of this metal in the extracellular space. The presence of zinc within the cell causes an increase in metallothionein, which is the major zinc-binding protein, and together they form a thermodynamically stable complex [40, 41]. Thus, low risk ways of increasing zinc bioavailability in the body can be safely considered.

In rats, rice fortified with zinc oxide or zinc carbonate is a feasible vehicle for zinc absorption, although zinc oxide displays lower bioavailability than zinc carbonate [42]. In young adults, zinc absorption from supplemental zinc citrate is comparable with that from zinc gluconate, but higher than from zinc oxide [43]. It is already known that zinc can be absorbed from topical (non-nano) zinc oxide by human skin in small quantities (nano forms of zinc oxide are not associated with significant zinc absorption) [44]. One of our recent studies suggests that zinc is absorbed by the human body from our suncare products (all with the same basic formula containing a medicinal form of zinc oxide) in sufficiently large quantities with regular use [45].

So, recently, when our company received an inquiry from Health Canada regarding any innovations that may benefit Canadian health workers at this critical time during the novel coronavirus pandemic, the answer was that we do have a product that may be useful to medical professionals and health workers in the field. It is a natural, award-winning suncare product specially formulated to block apoptotic sunburn (Skin Protector Plus). Its active ingredient is a non-nano, medicinal form of zinc oxide. The novel thing about this product is that it appears to be an efficient delivery system for boosting zinc levels in the whole body in a relatively short period of time. There is no toxicity associated with this product due to the use of high grade zinc oxide and natural ingredients. Since it is so safe and contains no harsh chemicals (already tested on human volunteers), no pre-clinical trials would be required to test

its efficacy in protecting subjects from COVID-19 in a clinical study. The objective of such a comprehensive study would be to test and confirm the hypothesis outlined above, *in vivo*; namely, if maximum zinc levels are maintained in the human body via percutaneous zinc absorption from a topically applied zinc oxide cream, then it may provide one suitable defense against SARS-CoV-2 infection. Although oral supplementation is also an option, this type of topical application on the surface of the skin may be a faster method of ensuring even zinc distribution throughout the body and delivery to the various potential points of viral entry. Moreover, it may actually provide a physical barrier or blockade against entrance of the virus into the body by allowing suffusion and accumulation of zinc pools directly beneath the skin.

#### **6.3 Chloroquine/quinine**

Quinine, an alkaloid derived from the bark of the cinchona tree, is most commonly found in South America, Central America, the islands of the Caribbean, and parts of the western coast of Africa. It is an important antimalarial drug and a synthetic form with a similar mode of action is known as chloroquine [46]. Chloroquine has been reported to inhibit the SARS-CoV-1 virus in infected cell cultures *in vitro* at doses equivalent to those used in the treatment of acute malaria in humans. Its antiviral effect appears to depend on the fact that chloroquine is a weak base that increases the pH of acidic vesicles when added extracellularly. The nonprotonated portion of chloroquine enters the cell where it becomes protonated and concentrated in acidic, low-pH organelles such as endosomes, Golgi vesicles, and lysosomes. The subsequent antiviral activity of the chloroquine depends partly on the extent to which a particular virus utilizes endosomes for entry into the cell [47]. In addition, this drug appears to interfere with terminal glycosylation of the angiotensin-converting enzyme 2 (ACE-2) cellular receptor, which is engaged by the virus for extracellular binding. This step may have a negative effect on the ability of the virus to gain entry into the host cell and, therefore, to initiate its replication cycle. Thus, infection may be deterred at clinically admissible concentrations [48]. Chloroquine also displays an immunomodulatory activity by suppressing the production and release of tumour necrosis factor alpha and interleukin 6 [49].

Furthermore, chloroquine was demonstrated to have strong antiviral activity against HCoV-OC43 *in vitro*. The anticoronaviral properties of chloroquine were also tested against HCoV-OC43 infection in newborn mice *in vivo.* Treatment with daily doses of chloroquine were found to have a long-lasting protective effect against lethal coronavirus OC43 infection in the newborn mice [1].

These favourable results suggest that chloroquine may be considered for use at antimalarial doses in the prevention of infections caused by coronaviruses, particularly SARS-CoV-2, which utilizes ACE-2 receptors in order to gain entry into host cells like its close relative, SARS-CoV-1.

#### **6.4 Glycyrrhizic acid**

Licorice root has been a commonly used ingredient in both Ayurvedic and traditional Chinese medicine for centuries, particularly in cough and cold remedies. Twenty triterpenoids and nearly three hundred flavonoids have been isolated from this herb. Scientific studies have shown that these metabolites possess many pharmacological activities including antiviral, antimicrobial, anti-inflammatory, and anti-tumour properties. However, glycyrrhizic acid or glycyrrhizin (GL), 18*β*-glycyrrhetinic acid (GA), liquiritigenin (LTG), licochalcone A (LCA), licochalcone E (LCE) and glabridin (GLD) are the main active components which possess antiviral and antimicrobial activities [50].

**19**

*Assembling an Anti-COVID-19 Artillery in the Battle against the New Coronavirus*

It has been known for some time that glycyrrhizic acid extracted from licorice (*Glycyrrhiza glabra)* root is active against viruses. This chemical is able to disrupt the growth and cytopathology of several unrelated DNA and RNA viruses without harming the host cell or its ability to replicate. Glycyrrhizic acid has also been demonstrated to inactivate herpes simplex virus particles irreversibly [51].

In a more recent study, the anti-SARSCoV activity of 15 glycyrrhizic acid deriva-

tives was tested. Glycyrrhizin was shown to inhibit SARS-CoV-1 replication *in vitro* [52]. GL has also been reported to act by inhibiting viral gene expression and replication, reducing adhesion force and stress, and reducing High mobility group box 1 protein (HMGB1) binding to DNA. In addition, GL can enhance host cell activity by blocking the degradation of I*κ*B, activating T lymphocyte proliferation and/or suppressing host cell apoptosis [50]. Thus, the potential for this licorice root

Isoflavones and their related flavonoid compounds, particularly genistein, exert antiviral properties against a wide range of DNA and RNA viruses *in vitro* and *in vivo* [53]. The biological properties of the flavonoids are well studied, but the mechanisms of action underlying their antiviral properties are not fully understood. Isoflavones appear to have a combination of negative effects on viruses including affecting virus binding, entry, replication, viral protein translation and formation of certain viral envelope glycoprotein complexes. A variety of host cell signalling processes can also be affected by isoflavones including induction of gene transcription factors and secretion of cytokines. All these effects are dependent on dose, frequency of administration, and different combinations of isoflavones employed in bioassays *in vitro*. Genistein may be able to mimic the action of 17-beta-estradiol [E2] due to its similar structure or to act as an E2 antagonist and its activity as a broad-spectrum tyrosine kinase inhibitor may contribute to its ability to influence estrogen receptor-independent mechanisms [54]. Despite their unique effect on immune function and anti-inflammatory activity, there is still a lack of data confirming the antiviral efficacy of such soy isoflavones *in vivo* against coronaviruses and other viruses thereby forming a worthwhile subject for

At least seven human coronaviruses have been described to date including SARS-CoV-2, which is closely related to and resembles SARS-CoV-1 in many respects. Both viruses bind to ACE-2 receptors on human cells. ACE2 is a membrane-associated aminopeptidase that converts angiotensin II to angiotensin 1–7 and plays a general role in the cleavage of peptides. Expression of ACE2 in human tissues correlates with known sites of SARS-CoV-1 infection including lungs (particularly airway epithelia), heart, kidneys, small intestine, testes, and vascular endothelia. These same tissues overlap with known sites of SARS-CoV-2 infection

A cluster of unexplained pneumonia cases were first reported in Wuhan, China and, a few days later, the cause of this pneumonia was identified as a new member of the coronavirus family. SARS-CoV-2 infection appears to be associated with a puzzling array of symptoms and complications. The major symptoms noted in China were fever (88%) and dry cough (67.7%), while rhinorrhea (4.9%) and gastrointestinal symptoms (diarrhea 4–14%) were less common. A majority of patients

component (GL) against SARS-CoV-2 infection is plausible.

*DOI: http://dx.doi.org/10.5772/intechopen.95100*

**6.5 Genistein & soy isoflavones**

biochemical study.

**7. Summary**

in humans.

*Assembling an Anti-COVID-19 Artillery in the Battle against the New Coronavirus DOI: http://dx.doi.org/10.5772/intechopen.95100*

It has been known for some time that glycyrrhizic acid extracted from licorice (*Glycyrrhiza glabra)* root is active against viruses. This chemical is able to disrupt the growth and cytopathology of several unrelated DNA and RNA viruses without harming the host cell or its ability to replicate. Glycyrrhizic acid has also been demonstrated to inactivate herpes simplex virus particles irreversibly [51].

In a more recent study, the anti-SARSCoV activity of 15 glycyrrhizic acid derivatives was tested. Glycyrrhizin was shown to inhibit SARS-CoV-1 replication *in vitro* [52]. GL has also been reported to act by inhibiting viral gene expression and replication, reducing adhesion force and stress, and reducing High mobility group box 1 protein (HMGB1) binding to DNA. In addition, GL can enhance host cell activity by blocking the degradation of I*κ*B, activating T lymphocyte proliferation and/or suppressing host cell apoptosis [50]. Thus, the potential for this licorice root component (GL) against SARS-CoV-2 infection is plausible.

#### **6.5 Genistein & soy isoflavones**

*Some RNA Viruses*

**6.3 Chloroquine/quinine**

its efficacy in protecting subjects from COVID-19 in a clinical study. The objective of such a comprehensive study would be to test and confirm the hypothesis outlined above, *in vivo*; namely, if maximum zinc levels are maintained in the human body via percutaneous zinc absorption from a topically applied zinc oxide cream, then it may provide one suitable defense against SARS-CoV-2 infection. Although oral supplementation is also an option, this type of topical application on the surface of the skin may be a faster method of ensuring even zinc distribution throughout the body and delivery to the various potential points of viral entry. Moreover, it may actually provide a physical barrier or blockade against entrance of the virus into the body by allowing suffusion and accumulation of zinc pools directly beneath the skin.

Quinine, an alkaloid derived from the bark of the cinchona tree, is most commonly found in South America, Central America, the islands of the Caribbean, and parts of the western coast of Africa. It is an important antimalarial drug and a synthetic form with a similar mode of action is known as chloroquine [46]. Chloroquine has been reported to inhibit the SARS-CoV-1 virus in infected cell cultures *in vitro* at doses equivalent to those used in the treatment of acute malaria in humans. Its antiviral effect appears to depend on the fact that chloroquine is a weak base that increases the pH of acidic vesicles when added extracellularly. The nonprotonated portion of chloroquine enters the cell where it becomes protonated and concentrated in acidic, low-pH organelles such as endosomes, Golgi vesicles, and lysosomes. The subsequent antiviral activity of the chloroquine depends partly on the extent to which a particular virus utilizes endosomes for entry into the cell [47]. In addition, this drug appears to interfere with terminal glycosylation of the angiotensin-converting enzyme 2 (ACE-2) cellular receptor, which is engaged by the virus for extracellular binding. This step may have a negative effect on the ability of the virus to gain entry into the host cell and, therefore, to initiate its replication cycle. Thus, infection may be deterred at clinically admissible concentrations [48]. Chloroquine also displays an immunomodulatory activity by suppressing the production and release of tumour necrosis factor alpha and interleukin 6 [49]. Furthermore, chloroquine was demonstrated to have strong antiviral activity against HCoV-OC43 *in vitro*. The anticoronaviral properties of chloroquine were also tested against HCoV-OC43 infection in newborn mice *in vivo.* Treatment with daily doses of chloroquine were found to have a long-lasting protective effect

against lethal coronavirus OC43 infection in the newborn mice [1].

cells like its close relative, SARS-CoV-1.

antiviral and antimicrobial activities [50].

**6.4 Glycyrrhizic acid**

These favourable results suggest that chloroquine may be considered for use at antimalarial doses in the prevention of infections caused by coronaviruses, particularly SARS-CoV-2, which utilizes ACE-2 receptors in order to gain entry into host

Licorice root has been a commonly used ingredient in both Ayurvedic and traditional Chinese medicine for centuries, particularly in cough and cold remedies. Twenty triterpenoids and nearly three hundred flavonoids have been isolated from this herb. Scientific studies have shown that these metabolites possess many pharmacological activities including antiviral, antimicrobial, anti-inflammatory, and anti-tumour properties. However, glycyrrhizic acid or glycyrrhizin (GL), 18*β*-glycyrrhetinic acid (GA), liquiritigenin (LTG), licochalcone A (LCA), licochalcone E (LCE) and glabridin (GLD) are the main active components which possess

**18**

Isoflavones and their related flavonoid compounds, particularly genistein, exert antiviral properties against a wide range of DNA and RNA viruses *in vitro* and *in vivo* [53]. The biological properties of the flavonoids are well studied, but the mechanisms of action underlying their antiviral properties are not fully understood. Isoflavones appear to have a combination of negative effects on viruses including affecting virus binding, entry, replication, viral protein translation and formation of certain viral envelope glycoprotein complexes. A variety of host cell signalling processes can also be affected by isoflavones including induction of gene transcription factors and secretion of cytokines. All these effects are dependent on dose, frequency of administration, and different combinations of isoflavones employed in bioassays *in vitro*. Genistein may be able to mimic the action of 17-beta-estradiol [E2] due to its similar structure or to act as an E2 antagonist and its activity as a broad-spectrum tyrosine kinase inhibitor may contribute to its ability to influence estrogen receptor-independent mechanisms [54]. Despite their unique effect on immune function and anti-inflammatory activity, there is still a lack of data confirming the antiviral efficacy of such soy isoflavones *in vivo* against coronaviruses and other viruses thereby forming a worthwhile subject for biochemical study.

#### **7. Summary**

At least seven human coronaviruses have been described to date including SARS-CoV-2, which is closely related to and resembles SARS-CoV-1 in many respects. Both viruses bind to ACE-2 receptors on human cells. ACE2 is a membrane-associated aminopeptidase that converts angiotensin II to angiotensin 1–7 and plays a general role in the cleavage of peptides. Expression of ACE2 in human tissues correlates with known sites of SARS-CoV-1 infection including lungs (particularly airway epithelia), heart, kidneys, small intestine, testes, and vascular endothelia. These same tissues overlap with known sites of SARS-CoV-2 infection in humans.

A cluster of unexplained pneumonia cases were first reported in Wuhan, China and, a few days later, the cause of this pneumonia was identified as a new member of the coronavirus family. SARS-CoV-2 infection appears to be associated with a puzzling array of symptoms and complications. The major symptoms noted in China were fever (88%) and dry cough (67.7%), while rhinorrhea (4.9%) and gastrointestinal symptoms (diarrhea 4–14%) were less common. A majority of patients (81%) had only mild symptoms (no pneumonia or mild pneumonia). Among patients with more pronounced symptoms, 14% experienced severe symptoms while 5% were critically ill with respiratory failure, septic shock, or multiorgan dysfunction or failure.

New data suggests that SARS-CoV-2 may spread via the bloodstream to infect other organs. In addition to the lungs, other target organs can include the heart, liver, brain, kidneys, and spleen. It also appears that COVID-19 may predispose patients to venous thromboembolism in several different ways including via endothelial dysfunction and promotion of a procoagulatory state. In fact, it was found that a significant percent of critically ill patients experienced myocardial injury from the infection and it has been concluded that COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilization, and diffuse intravascular coagulation. The COVID-19 pandemic is associated with various neurological symptoms and complications including anosmia, hypogeusia, seizures, and stroke, as well. COVID-19 complications in the brain can include delirium, inflammation, and encephalitis. Despite initial reports that children were unaffected by the novel coronavirus, it has emerged that pediatric patients are susceptible to a COVID-19-associated multisystem inflammatory syndrome that can cause serious inflammation of the blood vessels.

Several internal risk factors have been identified for SARS-CoV-2 infection. The main ones include age (older adults are more vulnerable to serious infection by the virus), gender (the virus is significantly more deadly in men than in women), obesity, heart disease, diabetes, cancer status, and smoking. However, there is no convincing evidence to date that any particular ethnic group displays a stronger genetic susceptibility to the virus (although, there may be a possible link to an inherited Neanderthal gene locus). Nevertheless, specific genetic variants such as those for the gene that encodes a protein that interacts with the ACE-2 receptor may be involved in determining individual patient responses to the disease. Simultaneously, external risk factors like environmental pollution, social conditions such as crowding, and frequency of exposure to infected persons also seem to play an important role.

Reports of re-infection in recovered humans is a surprising aspect of this virus. Recently, a team from the University of Hong Kong reported the first case of reinfection of COVID-19 within a period of approximately four and a half months. Genomic analyses confirmed that the patient had re-infection instead of persistent viral shedding from first infection. Moreover, there was a difference of 24 nucleotides between both viruses that infected the patient suggesting two different viral strains were involved [55].

Even though the virus is associated with positive COVID-19/COVID-19 antibody and high C-reactive protein test results, antibody levels may decline soon after infection. Consequently, it is quite possible that a lasting resistance to the virus will not be achievable. In the event that long-term immunity cannot be induced to the novel coronavirus by a vaccine, an annual, bi-annual, or even tri-annual inoculation may be required (current data suggests that antibodies begin to decrease or disappear three months after infection). This means that other modes of protection and prevention like supplementation may be more relevant in this case. Some candidates include Vitamin D, zinc, chloroquine/quinine, glycyrrhizic acid, and genistein due to anti-viral properties such as the ability to inhibit replication and reproduction of coronaviruses.

Scientists have concluded that drastic social distancing, quick detection and isolation of infected individuals and travel restrictions were the most effective steps for containment of COVID-19 in China. Genome sequencing has also helped to track and control COVID-19 infections quickly. However, if people do not

**21**

Canada

**Author details**

Chanda Siddoo-Atwal1,2,3

1 University College London, London, United Kingdom

\*Address all correspondence to: moondustcosmetics@gmail.com

3 President and Primary Biochemist of Moondust Cosmetics Ltd, West Vancouver,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Simon Fraser University, Burnaby, Canada

provided the original work is properly cited.

*Assembling an Anti-COVID-19 Artillery in the Battle against the New Coronavirus*

oxide crème formulation applied to the skin underneath [56].

continue to be careful, certain places may become vulnerable to further rounds of this disease. WHO recently reported that coronavirus infections among younger populations were skyrocketing. The proportion of cases in teens and young adults increased six-fold, while the proportion in young children and babies increased seven-fold by August. This may be attributable in part to the resurgence of large parties and social gatherings attended by young people following the relaxation of restrictions during the summer. Therefore, it seems very likely that the denouement of the COVID-19 story will be largely dictated by our social habits and ability to adapt to a new set of societal norms and conditions. This will include wearing face masks in public places, possibly, with a thin zinc coating along with a special zinc

*DOI: http://dx.doi.org/10.5772/intechopen.95100*

#### *Assembling an Anti-COVID-19 Artillery in the Battle against the New Coronavirus DOI: http://dx.doi.org/10.5772/intechopen.95100*

continue to be careful, certain places may become vulnerable to further rounds of this disease. WHO recently reported that coronavirus infections among younger populations were skyrocketing. The proportion of cases in teens and young adults increased six-fold, while the proportion in young children and babies increased seven-fold by August. This may be attributable in part to the resurgence of large parties and social gatherings attended by young people following the relaxation of restrictions during the summer. Therefore, it seems very likely that the denouement of the COVID-19 story will be largely dictated by our social habits and ability to adapt to a new set of societal norms and conditions. This will include wearing face masks in public places, possibly, with a thin zinc coating along with a special zinc oxide crème formulation applied to the skin underneath [56].
