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Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 122-126

A cinnamon-derived procyanidin type-A compound: A potential candidate molecule against coronaviruses including COVID-19

Director, Trigonella Labs Private Limited, Sydney, Australia

Date of Submission30-Dec-2020
Date of Acceptance27-Jan-2021
Date of Web Publication18-Mar-2021

Correspondence Address:
Dr. Dilip Ghosh
Nutriconnect, 8 Rye Street, Stanhope Gardens, NSW 2768
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jacr.jacr_89_20

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How to cite this article:
Ghosh D. A cinnamon-derived procyanidin type-A compound: A potential candidate molecule against coronaviruses including COVID-19. J Ayurveda Case Rep 2020;3:122-6

How to cite this URL:
Ghosh D. A cinnamon-derived procyanidin type-A compound: A potential candidate molecule against coronaviruses including COVID-19. J Ayurveda Case Rep [serial online] 2020 [cited 2022 Aug 8];3:122-6. Available from: http://www.ayucare.org/text.asp?2020/3/4/122/311507

  Introduction Top

In the last few centuries, we experienced many global viral infections such as coronavirus (CoV), coxsackievirus, dengue virus, enterovirus 71, hepatitis B virus, hepatitis C virus (HCV), herpes simplex virus, human immunodeficiency virus (HIV), influenza virus, measles virus, and respiratory syncytial virus. Few of them are endemic or epidemic in nature and contained. But the recent progressive outbreaks of COVID-19 have shown limitations, as well as the importance of a high level of health-care system. We have seen unprecedented progress and cooperation globally in public-private partnerships made in immunization and drug development programs. Despite some initial progress, we are still not in a position to control this global outbreak. After decades of the first incidence of both Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS), we still have no working preventive vaccines and efficient antiviral therapies, probably due to the lack of persistent follow-up research and funding insufficiency.

Traditional herbal medicines and purified herbal extracts are always considered a rich resource for novel antiviral drug development for centuries.[1],[2],[3],[4] To control viral infection, the potential anti-viral drugs must target any phase of the viral life cycle, such as viral entry, replication, assembly, and release, as well as the mechanism, involved virus–host-specific interactions.[5] So, it is paramount important to identify of the antiviral mechanisms from these natural agents and that will have shed light on where they interact with the viral life cycle. Although not all products are tested in randomized blinded control trials, their safety and mechanism of actions are well defined.

  What is COVID-19 and Its Structure Top

Wuhan in Chinas Hubei province is a global political epicenter now and also an epicenter of the COVID-19 pandemic. This novel respiratory disease was first reported to the WHO Country Office in China, on December 31, 2019. Since the identification of the causative agent was not possible at starting phase, henceforth the first batch of cases were classified as “pneumonia of unknown etiology.” The etiology of this illness is now classified and attributed to a novel virus belonging to the CoV (SARS-CoV2) family and names as “COVID-19.” In November 2002 and September 2012, two additional CoV epidemics have occurred such as SARS-CoV in China and involving two dozen countries and the MERS-CoV that began in Saudi Arabia and spread to few countries, respectively.

“Emerging respiratory disease” outbreaks in this century is a major concern and the family of CoVs including recent COVID-19 have been identified as major pathogens.[6] Being a part of single-stranded RNA viruses (+ssRNA), zoonotic origin has been detected in different animal species and showed to acquire the ability to cross the species barriers to infect humans.[7] Scientists around the world have been trying to establish the disease dynamics of SARS-CoV2, but there is speculation that it also has an animal origin, probably several bat species, predominately horseshoe bats.

The CoV name is derived due to its crown-like appearance (coronam is the Latin term for crown) having spike glycoproteins on the envelope (under electron microscope). The subfamily orthocoronavirinae of the Coronaviridae family (order Nidovirales) classifies into four genera of CoVs: alpha CoV, beta CoV (betaCoV), delta CoV, and gamma CoV.[8] Wide range of animal species, including camels, cattle, civet cats, raccoon dogs and bats are infected by CoVs, which can cause respiratory, enteric, hepatic, and neurological diseases in humans after transmission. To date, seven human CoVs (HCoVs) have been identified which have a clear source of zoonotic origin. Some HCoVs have been identified in the mid-1960s, while others were only detected in the last few decades.[6]

The beta CoVs genera from where the SARS-CoV2 originated and assumed to have horseshoe bats origin. The shape is round or elliptic and often pleomorphic form, and a diameter of approximately 60–140 nm [[Figure 1], Courtesy-Jason Roberts, Doherty Institute, source-Internet]. The SARS-CoV2 is sensitive to ultraviolet rays and heat. Based on the recent extensive studies, it is recommended to inactivate these viruses effectively by lipid solvents including ether (75%), ethanol, chlorine-containing disinfectant, peroxyacetic acid, and chloroform except for chlorhexidine.[9]
Figure 1: SARS-CoV2 structure

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  Pathophysiology Top

A recent review[10] gave an overview of the pathophysiology of SARS-CoV2 infection, mostly covering the immunity, inflammation, and intervention perspectives. They described “the interaction of SARS-CoV2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression”. The nonstructural protein (nsp) and structural proteins of SARS-CoV2 are supposed to be responsible for pathophysiology and virulence mechanisms. The host innate immune response has shown to be blocked by nsp.[11] The virus pathogenicity is closely linked with viral assembly and release and the structural proteins of the envelope have a crucial role in this promotion. Two subunits (S1 and S2) of the spike glycoproteins resulting in the link to host receptors.[12] A fusion peptide in S2 subunit of SARS-CoV2 could be a target molecule for antiviral (anti-S2) compounds. Whereas, a Receptor-Binding Domain (RBD) in the S1 subunit is spearheading the identification and binding process with the cell surface receptor [Figure 2]. Interestingly, the spike receptor-binding domain resemblances only a 40% amino acid with other SARS-CoVs.
Figure 2: Binding pattern of S1 and S2 of SARS-CoV2 to ACE2 receptor

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  Entry Inhibitors: A Crucial Step to Block Viral Infection Top

In recent years, the significant advancement of antiviral drug research has empowered drug development scientists to mitigate or relieve the debilitating effects of many viral pathogens,[13] although sometimes “repurposing” of clinically developed drugs for one virus is using to combat another viral disease. COVID-19 is a unique example where many clinical scientists are trialing “repurposing” drugs, such as Hydroxychloroquine, Azithromycin, Remdesivir, Favipiravir etc. New drug development takes many years before to go the clinic, in this global COVID-19 scenario, instead of designing and synthesizing de novo drug leads, many alternative approaches are exploring around the world. The discovery of new viral entry inhibitors is one of them.[14] The large diversity of novel natural compounds, particularly diverse botanical extracts have been exploring for the search of new anti-viral compounds. Historically, many highly effective drugs (for example Aspirin and Taxol®) have been isolated from the ethnopharmacological origin and these are pillars of traditional Chinese medicines and Ayurvedic pharmacopeia.[15] Viral entry inhibitors offer a new and promising ways to mitigate viral infections from a therapeutic perspective.

In the present review, I am demonstrating new drug discovery history from small molecules of botanical extract (Cinnamon) on wide ranges of respiratory viruses. Researches are targeting the binding mechanisms to block viral capture and entry to the human body. This standardized unique Cinnamon extract has been tested on several virus models and is currently under investigation against COVID-19 (pre-clinical) as a new drug candidate program in Australia.

  Cinnamon: A Journey from Ayurveda to Modern Medicine Top

Cinnamon (Cinnamomum verum; Cinnamomum zeylanicum) is a small evergreen tree, 10–15 meters tall, belonging to the family Lauraceae. C. verum is native to Sri Lanka and South India, but it is also considered to be native to the Tenasserim Hills of Myanmar. This has already been introduced pan-tropically in the 1700s. The flowers have a greenish color and have a distinct odor. The fruit is small berry-like purple color with a single seed. Its district flavor is due to the presence of aromatic essential oil which makes up 0.5%–1% of its composition. The bark of cinnamon has been used predominantly as a spice and tea but also used as one of the key components of oriental herbal remedies for centuries for the common cold, cardiovascular disease, chronic gastrointestinal and gynecological disorders.[16] Cinnamon is an essential component in the Ayush Kwath formulated by the Ministry of AYUSH to fight against COVID-19 pandemic.[17] In the past decade, extensive studies on the structural and pharmacological activities of the cinnamon bark have been conducted, demonstrating modern medicinal activities beyond of its traditional health benefits.[18]

Entry inhibitors with a new mode of action: A game-changer in anti-SARS-CoV2 therapy

In recent years, there is a huge momentum at both the federal and corporate level for the development of antiviral drugs in a new way to mitigate or relieve the debilitating effects of many viral pathogens, including COVID-19.[6],[13] The unique example is the discovery of zidovudine as an effective viral cycle disrupter of the HIV type-1 (HIV-1), which has significantly influenced the quality and extension of the lives of many HIV-1-positive individuals around the world.[13] But unfortunately, “the regular use of zidovudine, as well as other HIV-1 reverse transcriptase inhibitors, protease inhibitors and highly active antiretroviral therapy involving multidrug therapies, has led to the selection of resistant HIV-1 strains, making the control of HIV-1 viral load in seropositive and AIDS patients difficult.”[19] To avoid this, multi-component compounds such as cinnamon may possess some advantages in the case of drug-resistant virus. In addition, cinnamon is economically affordable in low-income HIV-affected countries and oral ingestible.

Cinnamon blocks leukocyte attachment

Cell migration is a crucial event during innate and adaptive immune responses by engaging leukocytes to the sites of acute or chronic inflammation.[20],[21] Inadequate assembly of leukocytes may affect inflammatory reaction and initiate pathological processes of inflammation.[20],[21] There are several cell surface proteins on this list. Both members of the integrin and selectin group of binding protein and carbohydrate, respectively, are extensively studied in this mechanism. Particularly, P-selectin in platelets and L-selectins of leukocytes, are known to participate in cell-cell adhesion and trafficking in blocking leukocyte attachment mechanism. Lin et al. demonstrated a reduction of the attachment of THP-1 to TNF-α activated HUVECs by particular cinnamon extract (IND02) under “shear flow.”[5] Human neutrophils attachment to E-selectin/ICAM-1-coated surface is also blocked by IND02 extract. The authors also showed that the treatment of IND02 easily detached the adherent neutrophils. They concluded for the first time “the IND02, a cinnamon-derived type A procyanidin molecule, reduces inflammatory responses by interaction with sialosides and blocking leukocyte adhesion to interacting sialosides.”[5]

Anti-HIV type-1 activity

Significant achievements in clinical outcomes have been done in recent decades, but the HIV pandemic still considers an important threat to public health. Blocking viral entry has been recently advocated as a very promising strategy to inhibit HIV-1 infection. Heparan sulfate (HS), CD4 and co-receptors (CCR5/CXCR4) are identified as important cell surface molecules for viral attachment and entry to cells, which are recognized by gp120.[14],[22],[23] Targeting these cell surface receptors offering multiple target sites for therapeutic intervention. Connell et al. demonstrated that IND02, a unique cinnamon extract containing rich of type A procyanidin trimer and pentamer polyphenols exhibited anti-vital activity against CXCR4 and CCR5 viruses at very low μM range.[23] Using surface plasmon resonance-based binding assay this group showed inhibition of HIV-1 glycoprotein from interacting with cellular HS, CD4 and a monoclonal antibody (mAb 17b). Interestingly, the IND02-trimer inhibited HIV-1 infection in “multinuclear activation of the galactosidase indicator” cells also showed in this study. This study showed a very promising roadmap to block viral attachment and mitigate the viral load.

Hepatitis C virus entry blocker

Chronic HCV infection is a major cause of liver disease worldwide and ultimately leads to liver transplantation. Many antivirals compounds from natural sources have been trialed and few of them demonstrated some level of success. Silymarin and silibinin (active molecule) from milk thistle Silybum marianum, shown very promising anti-HCV activity at several levels of the viral life cycle. Few recent publications demonstrated the efficient anti-HCV activity against multiple HCV strains and genotypes.[24],[25] They used relevant cell culture models without major cellular toxicity[24] demonstrated that IND02 cinnamon extract appears to inhibit HCV infection at even lower concentrations (EC50 of 2.06 μM) compared with other natural anti-HCV compounds such as silibinin and ECGC from green tea. Interestingly, IND02 had no effect on other stages of HCV replication except HCV entry, and most probably at post binding level. This study also showed the potential of cinnamon extract as viral entry blocker against ranges of viruses. Overall, the kinetic study showed more than 95% HCV infection inhibition, probably via alteration of viral fusion in endosomes.

  Discussion and Conclusion Top

The COVID-19 is affecting 213 countries and territories around the world and no sign of stopping. As of February 17, 2021 more than 108.8 million people has infected and claimed the lives of 2.4 million people worldwide. Within this horror, the findings published very recently in the cell,[26] hold a big promise on different treatment regimens for stopping early infection of the novel CoV. They highlighted new insights on SARS-CoV2 pathogenesis and its interactions at a cellular level. The ACE2- a protein on the surface of the cell membrane and the spike glycoproteins-is now at centre-stage of most SARS-CoV2 research. The interaction of these two molecules is also link with both cardiovascular disease and lung failure.

Plants are an integral part of the ancient civilisations such as Indian, Chinese and Egyptian cultures for centuries and plant anthropologists can trace back the usage of these natural remedies and medicines as far as the neanderthal period.[27] In the last two decades, scientists have been pursuing the anti-viral potential of compounds isolated from Cinnamon.[28] demonstrated the inhibitory effect of trans-cinnamaldehyde (CA) on the growth of influenza A/PR/8 virus in vitro and in vivo. They applied this compound directly on airways of infected mice. This led to a significant reduction in virus load in the lungs and subsequent remission of influenza virus-induced pneumonia. During a similar time[29] found that the butanol fraction (containing procyanidin A2 and procyanidin B1) of Cinnamomi Cortex (CC/Fr. 2) possessed moderate anti-viral activity in wild-type SARS CoV (wtSARS-CoV) and HIV/SARS-CoV S pseudovirus infections.

Based on many recent studies it has been demonstrated that extract of cinnamon-derived procyanidin type A compound (IND02) would presumably inhibit COVID-19 at the entry-level due to its high affinity toward ACE2 receptor and also via binding to glycans on the viral spike protein. Few leading studies are currently undergoing at the Virology Department, National Taiwan University Hospital, Strasbourg University, France and at the Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai with different objectives as follows:

  1. The antiviral action of IND02 against oseltamivir-resistant H1N1 and H3N2 viruses
  2. The entry inhibition of HCV at the post binding step of viral entry through a blockade of ACE2-Spike protein complex formation
  3. The binding kinetics and affinity of IND02 to the RBD of the COVID-19 spike protein by the biolayer interferometry binding assay and enzyme-linked immunosorbent assay.

We believe based on the many mechanistic and preclinical studies, IND02 is expected to exert its action both on the viral entry as well as on the host immune modulation[30] via reducing the oxidative stress and injury to the respiratory milieu in the infected patients. Nasal spray formulation of IND02 could offer prophylactic benefits against COVID-19 infection.

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Conflicts of interest

There are no conflicts of interest.

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