CINCHONA EXHIBITS CANDIDATES AS A COMPLEMENTARY ANTIVIRAL ACTIVITY FOR SARS-COV-2: A NARRATIVE REVIEW

CINCHONA EXHIBITS CANDIDATES AS A COMPLEMENTARY ANTIVIRAL ACTIVITY FOR SARS-COV-2: A NARRATIVE REVIEW

Manikantan Pappuswamy *, Arun Meyyazhagan and Aditi Chaudhary

Department of Life Sciences, CHRIST (Deemed to be University), Bangalore, Karnataka, India.

ABSTRACT: Aim and Objective: The coronavirus disease 2019 (COVID-19) pandemic, caused by the coronavirus-2 (SARS-CoV-2) that causes severe acute respiratory syndrome, is the world's most serious health issue. COVID-19 is currently without a precise and successful antiviral treatment. Phytochemicals provide a ray of hope for public well-being amid the pandemic, and much study is being done on them. Materials and Methods: Cinchona bark contains phytochemicals that have been used as antiviral agents against various viruses because they can suppress various viruses via various mechanisms of direct inhibition at the viral entry point and replication stages via immunomodulation potentials. Cinchona bark and its components have also been shown to have promising antiviral properties against SARS-CoV-2, according to recent data. This narrative analysis summarizes cinchona phytochemical agents, their mechanisms of action, and possible antiviral behaviours against the SARS-CoV-2 virus. Results and Discussion: Medicinal plants and their extracts and herbs have shown positive results in combating SARS-CoV-2 infection and could help treat COVID-19 patients as alternatives to care under phytotherapy approaches during this disastrous pandemic scenario. Conclusion: Finally, we presented the advantages and disadvantages of using cinchona herbal medicine during the COVID-19 pandemic, as well as some observations and suggestions.

Keywords: COVID-19, Herbal medicine, Cinchona, Anti-Viral agents, SARS-CoV-2

INTRODUCTION: In Wuhan, China, a major global epidemic of coronavirus 2 that causes Severe Acute Respiratory Syndrome (SARS) started in December 2019, with 24 March 2020 records originating from 195 countries, resulting in 3.1 million deaths ¹. On March 11, 2020, the WHO declared it a pandemic and as of March 21, 2020, the viral pathogenesis and replication processes are unclear, making treatment difficult ².

No new medicines or vaccines for Covid-19 yet exist, though novel antiviral drugs are being tested. A lack of prescription medication availability has fueled the need for plant-based medicinal options, high costs, consumer expectations and alternative and folk medicine practices ³. Herbal preparations have been used to cure a variety of diseases since ancient times and they continue to be an integral component of modern pharmacopeia.

According to the World Health Organization (WHO), conventional plant-based drugs are now used by 80% of the population of developed countries. Sadly, with the rise of mass-produced pharmaceuticals, much of mankind's arcane historical ethnobotanical knowledge has been lost ^{4, 5}. Oral practices have been neglected and their present cultural significance has been ignored. For example, the Susruta Samhita and Traditional Chinese Medicine have both been collectively editorialized and debunked as pseudoscience ⁶. Despite this, isolated plant constituents are already used in 25% of commonly used medications and can help to compensate for the global shortage of essential medicines. Structure of SARC-CoV2. Within a matrix protein capsid, COVID-19 are enveloped spherical particles containing single-stranded RNA and a nucleoprotein. Glycoprotein projections in the form of clubs can be found on the envelope. Any coronaviruses include the hem-agglutinin-esterase protein (HE) ⁷.

FIG. 1: STRUCTURE OF SARS-COV2 SOURCE FROM BIOWIKI. (http://ruleof6ix.fieldofscience.com/2012/09/a-new-coronavirus-should-you-care.html).

Coronaviruses have the largest genomes of any known Ribo Nucleic Acid (RNA) virus, varying from 32 to 43 percent G + C material. There are different numbers of small Open Reading Frames (ORFs) within the conserved genes and downstream of the nucleocapsid gene in different coronavirus lineages Fig. 1. A special N-terminal fragment inside the spike protein is one of the viral genome's distinguishing features. S, E, M, and N are the 5′–3′ order of all coronaviruses' main structural protein genes ⁸.

Pathogen City of SARS-CoV2: SARS-CoV2 needs a specific receptor, the Angiotensin Converting Enzyme 2 (ACE2) receptor, to enter the host cell Fig. 2.

FIG. 2: ATTACHMENT OF SARS-COV [SOURCE: LEILA MOUSAVIZADEH, SORAYYA GHASEMI, GENOTYPE AND PHENOTYPE OF COVID-19: THEIR ROLES IN PATHOGENESIS. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY AND, INFECTION. 2020]

The association between the virus's spike protein and the host cell's ACE2 receptor begins during the virus's internalization process ^{9, 10}. The activation mechanism begins when the receptor-binding domain (RBD) inside the S1 region of the virus S protein interacts with the ACE2 receptor ¹¹. After this encounter, the virus must reach the host cell's cytosol, which is accomplished by acid-dependent proteolytic cleavage of the spike protein by a cathepsin protease enzyme. The internalization process begins with the coronavirus fusing with the host cell membrane ¹².

FIG. 3: THE ENTRY POINT OF SARS-COV2 IN A HOST CELL

The spike protein is cleaved in two places inside the S2 part. To distinguish the S protein's RBD and fusion domains. At S2, the peptide bond may be revealed or cleaved ^{13, 14}. Within acidic endosomes, the virus and the host cell typically fuse together. Few viruses can also fuse the outer membrane Fig. 3. The cleavage exposes the fusion peptide that incorporates into the membrane at S2. Two heptad repeats in S2 are then bound together to form an antiparallel six-helix bundle. The viral and host cell membranes fuse during bundle development, resulting in viral genome fusion and release into the cytoplasm ¹⁵.

Immunity against Infection: The opening spot of SARS-CoV-2 contamination is uncertain, also the pathogenesis of COVID-19 is being investigated. Since COVID-19 is a pulmonary condition, it usually only affects the lungs of most patients. However, psychiatric signs can worsen in certain people with comorbidities ¹⁶. Mode of infection through direct contact with human to human. Close contact, like coughing or sneezing by an infected person or interactions with health workers and COVID-19 patients, raises the risk of infection through droplets. This disease has a 2–14-day incubation cycle, which transmits very successfully ¹⁷. As a result of this form of infection, the disease's rate of dissemination varies, implying that the infected person will affect 2.2 and 2.6 individuals ¹⁸. In patients treated with SARS-CoV-2, the innate immune state is uncertain ¹⁹. According to a study, COVID-19 patients had increased neutrophils, interleukin (IL-6), and C-reactive protein (CRP) levels and a decrease in lymphocytes. How successful the innate immune system is against viruses is determined by the efficacy of the interferon (IFN) type 1 reaction. IFN has been related to viral replication, the triggering of adaptive immune responses 20, and its downstream consequences.

In COVID-19, this is how the innate immune response functions. Serological information on SARS-CoV-2 is also lacking. Nine days after the onset of COVID-19, most patients had a peak rise in immunoglobulin M (IgM), which then changed to immunoglobulin G ²¹. According to another research, viral load rises during then falls in the next. On day 10, major immunoglobulin levels started and rise ²². Several viruses may have recently triggered an evolving situation in some patients due to an immune response. The cytokine release syndrome, also known as a cytokine storm, is an emerging threat ²³. This disease develops after exposure to some influenza viruses ²⁴. It's even possible that it'll show up in SARS-CoV-2 infections. According to recent findings, a subset of COVID-19 patients may suffer from cytokine release syndrome (CRS) or cytokine storm syndrome (CSS). A cytokine storm is COVID-19's second leading cause of death ²⁵, due to an underrecognized hyperinflammatory syndrome that leads to several diseases. After virus infection, cytokine storm is a disease characterized by an active proinflammatory reaction and a loss of influence over an anti-inflammatory response ²⁶.

When tissue is damaged, the regenerative mechanism kicks in. It will cause severe organ modifications, and their cytokines will invade the bloodstream, causing a cytokine storm leading to multiorgan failure ²⁷. This cytokine storm in COVID-19 viral disease is characterized by a rise in interleukin, granulocyte-colony stimulating agent, IFN-c, inducible protein, monocyte chemoattractant protein, and tumour necrosis factor (TNF) ²⁸. Another research found that increased level of ILand MCP-1 ^{29, 30}. There are rising amounts of CRS in the CSS state when taken as a whole.

The above laboratory findings match SARS and other large respiratory viruses. Infection with COVID-19 can be aided by a cytokine storm ³¹. This cytokine storm may be the onset of viral sepsis and lung internal cell mass damage caused by inflammation. Complications include pneumonitis, acute respiratory distress syndrome, respiratory failure, and possibly death ³².

Cinchona Bark: In this pandemic climate, an anti-malarial treatment that left an indelible mark on those who took it is on everyone's lips; its effectiveness and advantages are fiercely debated. Some countries are using hydroxychloroquine, a synthetic modification of the "wonder drug" quinine, as an experimental therapy in the battle against COVID-19. Cinchona bark (CB) from the cinchona tree, a traditional natural source of quinine, was once used to make anti-viral chloroquine analogs, which are currently being studied against SARS-CoV-19 ^{33, 34}. On the other hand, the medicinal applications of quinine bark have largely been relegated to history with the emergence of modern industrial-scale drug synthesis. The theoretical application of CB as an acute anti-COVID-19 monotherapy is revisited in this article ³⁵. These cinchona medications' immunomodulatory auto-immune applications have popularized their use in the treatment of rheumatoid arthritis, chronic lupus, and juvenile rheumatoid arthritis ^{36, 37}.

Both chloroquine (CQ) and hydroxychloroquine (HCQ) have shown effectiveness in slowing the development of these diseases with minimal and reversible toxicity, particularly when used for a short period of time. The tolerability of CQ/HCQ and its low cost and immunomodulatory effects means that it may be used to treat viral infections and their inflammatory response ³⁸.

The anti-inflammatory effects of CB-derived chloroquine are also thought to temper immune hyperactivation reactions, which are common in HIV/AIDS patients ³⁹. This property may help regulate the cytokine storm that develops late in seriously affected patients. Quinine and CQ/HCQ have also been used for restless legs syndrome since they are thought to suppress motor endplate excitability and lengthen leg muscle latency ⁴⁰.

Structure of Cinchona Bark and its Derivatives: Quinine and related alkaloids (quinidine, cinchonidine,and cinchonine) found in the bark of Cinchona species. These quinoline alkaloids are isolated in multi-ton quantities on an industrial scale. Their configurations include quinoline and quinuclidine rings and a central hydroxyl group.

The arrangement of two essential stereo-geniccenters differs between the individual alkaloids also it has been used to cure malaria for over 400 years. While newer drugs such as chloroquine (1947) and artemisinin (1970s) have increasingly replaced them, their medicinal application is restricted to strains immune to drugs, also it can treat arrhythmias. Enantioselective synthesis and process of differentiation often use Cinchona alkaloids ⁴¹. There is yet to be a natural source for a dimeric alkaloid in this family. This,Cinchona alkaloid’sactive parts were used to create a large number of synthetic dimersindustry Fig. 4.

FIG. 4: MAJOR ALKALOIDS FROM CINCHONA BARK (SOURCE: BORATYŃSKI P. J. (2015). DIMERIC CINCHONA ALKALOIDS. MOLECULAR DIVERSITY)

Targets of Herbal Medicine: In this situation, where proper antiviral herbal therapy has not been prescribed for any infected patients, herbal medicines are widely used by many people in society. As in previous studies, a critical review of several papers from different publications relating to SARS-CoV-2 virus target molecules from plant sources was performed. At least herbal remedies have been identified as having the potential to inhibit the care of affected peoples. We also address the advantages and disadvantages of these candidates’ effects ^{42, 43}.

Cinchona against Covid 19: Cinchona sp. is a species (Chincona L., Raiatea) of Cinchona. Cinchona trees have significant impacts since a certain portion of compounds (alkaloid) contains an active molecule that cures the viral infection. Jesuit missionaries were the first to notice this beneficial influence, which spread across the globe ⁴⁴. The cinchona bark contains certain alkaloid compounds, which has been used to cure malaria for over a thousand years. Quinine works in a similar way to other synthetic drugs which contain anti-malarial activity ^45-47. Quinine compound contains sulphate is now the most widely used antibiotic.COVID-19 therapy medications are highly sought for in culture. Unacceptable Officials from the state had made remarks, anddoctors that frightened the people ⁴⁸.

As a result, people searched competitively for quinine-containing medications, acts of instead of a random response, the citizens were triggered.COVID-19 has a high prevalence and mortality rate in the whole world population ⁴⁹. This segment would discuss quinine's ability to act as an immunomodulator and an antiviral agent when a virus causes an illness. Additional information will also talk about the negative consequences ofquinine on people who have COVID-19 or don't have it.

FIG. 5: ANTI-VIRAL PROPERTIES OF CINCHONA BARK

Quinine gained popularity as a substitute for the anti-malarial medication chloroquine. Malaria medications were eventually repurposed as active inhibitors of viral infection, rather than as anti-malarial drugs. A broad body of evidence indicated that many anti-malarial medications have been studied and shown to have several benefits against viral infection ^50-52. Chloroquine, for example, has been shown antiviral in case of viral infection ^53-55. When treated with azithromycin, hydroxychloroquine increases the viral load in affected patients, according to a clinical trial Fig. 5.

On the other hand, recentevidence, quinine and chloroquine compounds, may contain active effect and elimination properties against the SARS virus ^{56, 57}. Fleisher et al. ⁵⁸ became the first to investigate the quinine effect as an anti-influenza virus infection. Furthermore, Baroni et al. described the antiviral effect of quinine in their study by blocking the gene expression ^59-61. Recent research consistently stated that quinine's suggested antiviral function involves viruses being killed indirectly. Previously, the effects of quinine sulphate on dengue virus-infected cells were investigated ^{62, 63}. The Viruses infecting host cells cause viral RNA to be released, interfering with normal protein synthesis. However, in the infected host cell, expression of RIG-I, a pathogen recognition receptor (PRR) that inhibits protein synthesis and thus blocks viral replication, increases minimally to promote the IFN-I signalling cascade rather than to elevate gene expression of IFN-stimulated genes ^64-66. In virus-infected cells, the RNase L pathway will delete ssRNA ^{67, 68}. Since, available data suggest that quinine inhibits and significant cytokine in deciding the seriousness of the viral infection, CSS does not occur after quinine administration in COVID-19 ^69-72. Although the cinchona tree extract does not induce CSS specifically, a systematic analysis published by Liles et al. found quinine causes a number of immune-mediated and toxic reactions ^{73, 74}. Quinine is rarely classified as an immunomodulatory agent but has antiviral immunostimulant and immunosuppressive properties. Quinine acts as an immunostimulator to inhibit viruses by efficiently increasing the synthesis of the well-known cytokine IFN ⁷⁵.

TABLE 1: MEDICINAL USES OF CINCHONA AND ITS DERIVATIVES

On the other hand, Quinine inhibits TNF- production and has an immunosuppressive effect. These two distinct behaviors can have a beneficial impact on COVID-19-infected individuals. However, it is not advised that healthy people take this herbal remedy regularly to avoid COVID-19 because it has the potential to produce a variety of negative side effects ⁷⁶ Table 1.

Safety Profile of Cinchona Bark's: Even though some experts believe quinine, CQ/HCQ is essentially safe, therapeutic, and over-therapeutic levels can have severe or fatal effects. Overdosing, whether intentional or unintentional, has been attributed to severe and often lethal heart arrhythmias, with fatal poisoning being of special concern in young children ⁹². There have also been reports of interactions with anti-clotting and anti-epileptic drugs ^{93, 94}. Dizziness, acute blindness, cardiomyopathy somnolence, suicidal ideation, and anaphylactic shock can occur with higher quinine doses, but these effects are reversible. In non-severe cases, though, most signs go away after you stop smoking ^{95, 96}. Aluminium-containing antacids, cholinesterase inhibitors, cimetidine, digoxin, neuromuscular disrupting agents, warfarin and other medications have also been linked to serious drug interactions.

Despite these side effects, synthetic CQ and HCQ analogues have been prescribed for more than 50 years, with reassuring acute administration protection profiles in the treatment of rheumatological diseases. Adverse CQ/HCQ side effects normally appear after several years of treatment, with macular retinopathy being the most severe of the side effects. Toxicity is often continuous rather than dose-dependent, and vision screening during treatment can help prevent irreversible retinal injury ^{97, 98}. According to another report, 500 mg of high-dose CQ a day for treating Rheumatology disorders whilst breastfeeding had a reassuring ocular defense profile ⁹⁹. Furthermore, Savarino and colleagues concluded that CQ/HCQ administration has a low risk/benefit ratio and a limited and preventable toxicity profile, especially in life-threatening conditions such as SARS and AIDS ^{100, 101}.

CONCLUSION: Based on the previous description, we infer that phytoremedies may have the capacity to secrete and regulate the cytokines that can interact and alter the internal molecular pathway relevant to the immune system. Herbal agents may be helpful in the war against COVID-19. Finally, patients should be advised that using a supplement substance to avoid a specific viral disease without the specific guidance of a clinician is still not recommended. A recommendation for the clinician is that, even though the patient is well, these medicines should be done with caution. This is because there has been a lot of conflicting information about these medicines. Thus, there's a chance that these therapies are linked to the induction of negative side effects. Furthermore, no preclinical or clinical trials of these herbal agents for COVID-19 have been conducted, necessitating further testing.

ACKNOWLEDGMENT: We would like to thank the Head of the Department, Department of Life Sciences, Christ (Deemed to be University), Bangalore, Karnataka, India, for providing us with the opportunity and requirements needed for the accomplishment of the research project. We also appreciate all study participants for volunteering to partake in the study.

Funding Source: Funding has not been received for this study.

CONFLICTS OF INTERESTS: Present study does not contain any conflict of interest.

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     Pappuswamy M, Meyyazhagan A and Chaudhary A: Cinchona exhibits candidates as a complementary antiviral activity for SARS-Cov-2: a narrative review. Int J Pharm Sci & Res 2023; 14(3): 1027-37. doi: 10.13040/IJPSR.0975-8232.14(3). 1027-37.

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