Pharmaceutical Resonance 2021 Vol. 3 Issue 2 · 2021. 1. 7. · Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, 411018, Maharashtra, India Sonali

Pharmaceutical Resonance 2021 Vol. 3 - Issue 2

© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 58

Sonali Shinde*, Asha Thomas

Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, 411018, Maharashtra, India

Sonali Shinde Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, 411018, Maharashtra, India eMail :[email protected]

REVIEW ARTICLE

PLANT DERIVED POLYPHENOL - CATECHIN AS A POTENTIAL ANTIVIRAL DRUG AGAINST COVID - 19

Abstract :

The current pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health issues. Medicinal plants, conventional & nonconventional foods have bioactive compounds that could be used to develop therapeutic drugs against Covid-19 with no or minimal side effects. During the pandemic, with a lot of emphasis on drug repurposing and development of traditional solutions to combat the infections, several researchers have screened numerous phyotconstituents using suitable in silico tools and in vitro assays to establish their efficacy against the Covid -19 virus. Such studies have revealed that Catechins (polyphenols) exhibit antiviral properties and these bioactive compounds might serve as potential anti-SARAS-CoV-2 lead molecules for further optimisation and drug development process to combat the COVID-19 pandemic.

Keywords : COVID-19, coronavirus, phytoconstituents, catechin, antiviral.

Corona Virus: Structure and major replication pathway

According to WHO (World Health Organization), the current Coronavirus pandemic situation is still grim with several countries across the globe reporting the indications of resurgence of the infections. Currently 7,22,21,634 confirmed cases with 16,12,014 mortality has been recorded in 216 countries globally. WHO declared it as a pandemic due to its high rate of transmission, unavailability of specific vaccines or medications to treat it.[1] The World Health Organization (WHO) named this pathogen as the 2019 novel coronavirus (2019-nCoV).[2] Coronavirus (2019-nCoV/SARS-CoV2)belonging to family Coronaviridae a novel new member of the betacorona virus genus is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV).[3-5] This is a positive-sense, single-stranded RNA, named as a SARS-CoV-2/COVID-19.[6] People get easily infected with this virus when they are in close contact with an infected person through droplet transmission( produced from cough or sneeze). Currently drugs like Remdesivir, Hydroxychloroquine, Lopinavir / Ritonavir, and other

HIV protease inhibitors are employed in treatment of patients. Few molecules and also the vaccine is in various stages of clinical research.[7,8]

W. Wang, et al. carried out the first whole-genome sequencing of 2019-nCoV, which helped researchers to quickly identify the virus in patients using reverse-transcription polymerase chain reaction (RT-PCR) methods. Later, X. Xu, P. Chen published the first article which revealed that 2019-nCoV belongs to the beta-coronavirus group, sharing ancestry with bat coronavirus HKU9-1, similar to SARS corona viruses, and that despite sequence diversity its spike protein interacts strongly with the human ACE2 receptor. [9]

The general morphology of coronavirus includes different structural proteins such as spike (S) protein, envelope (E) protein, membrane (M) protein and the nucleocapsid (N) protein.[10] Covid attacks human cells through its outer surface spike protein (glycoprotein in nature) with a receptor protein (s) present on the film of human cells. Fusion of virus with human cells occurs due to the binding of S1 subunit of viral protein S to human cell receptors.

In a very recent study, Lu et al., observed that external subdomain of S-glycoprotein of 2019-NCoV RBD is more similar to that of SARS-CoV, which suggests that this virus also targets the Angiotensin Converting Enzyme-2 (ACE2) receptors present in human cells. Therefore, it is presumed that ACE2, the cognate receptor of corona virus present in the host cells can be a specific target to inhibit the viral entry. [11]



In an extremely late investigation, R. Jeon and A. Prakash screened 72 FDA approved antiviral drugs against known targets of SARS-CoV2. They have used both human proteins and viral targets as a strategy. These chosen targets are already published with single drug interactions and also defined PDB structures. The following 7 targets were identified: viral spike (S) glycoprotein, viral nucleocapsid (N) protein, main protease (M pro) - an essential viral enzyme, (3CLPro) human endosomal cysteine protease Cathepsin L: required for viral entry, non-structural viral protein nsp-6 , the nsp12 and the two other cofactors nsp7- nsp8 complex of CoV-2 virus. The best binding sites of antiviral drugs with target proteins display a diverse range of binding affinities (6.23 ̶12.43 6 kcal/mol).

Herbals as anti-viral agents

For several decades, plants are being extensively explored to identify potent phytomoleclues for prevention and treatment of varied disorders. Approximately 2500 medicinal plant species have been recorded worldwide to treat various infections and diseases. Variety of medicinal plants has been reported to possess antiviral properties. Polyphenols, flavonoids, alkaloids, quinones, coumarins terpenes, proanthocyanidins, lignins, tannins, polysaccharides, steroids, thiosulfonates and saponins, are the major phytoconstituents, which have been observed to combat viral infections.[12-15] Several recent studies have suggested that natural polyphenolic compounds like catechins demonstrate a broad spectrum of activity against viruses such as Human Immunodeficiency Virus (HIV), Herpes Simplex Virus, Influenza virus, Hepatitis B and C viruses (HBV and HCV respectively)[16], Adenovirus, Zikavirus[17], Chikungunya virus (CHIKV)[18] Diverse mechanisms have been suggested to explain the antiviral activities catechins. Catechins have been documented to be a potential suppressor of viral entry and its replication. In wake of the COVID-19 pandemic, and reports of the possibility of exploring the potential of this molecule against the coronavirus, it was thought appropriate to gather and highlight the phytomolecule- catechin with special emphasis on its antiviral properties against the Covid-19 pathogen.

Catechin: Occurrence and properties

Catechin is a natural polyphenol, obtained as a plant secondary metabolite with antioxidant properties. It specifically belongs to the group of flavan-3-ols from the chemical family of flavonoids. Figure 1 represents the chemical structure of catechin and its derivatives.

Catechin present in tea is mostly comprised of epigallocatechin gallate (EGC), epigallocatechin (EGC), Theasinensin A (TSA), epicatechin gallate, and epicatechin (EC).[19] These constituents are

majorly available in green tea as compared to black tea. All the conventional and non-conventional food sources of catechins are summarized in Table 1.

Catechins are usually colorless crystalline substances, often with a bitter, astringent taste. They are easily soluble in polar solvents such as water and methanol. Catechins are comparatively unstable in nature and can be easily oxidized.

Catechins are mainly metabolized by phase 2 conjugation processes through glucuronidation and sulfation, mainly in the intestine whereas glucuronidation, sulfation and methylation also occur in the liver. Some conjugates are further methylated. Thus, the polarity of catechins increases and enhances its solubility and facilitates elimination through urine.[21]

Catechin: A promising anti - viral phytomolecule

Catechins exhibit antiviral effects against diverse viruses. In addition to antioxidant properties, they are reported for other pharmacological activities, such as the ability to lower glucose, lipid and uric acid (UA) levels.

In a study carried out by J. Dandapat and co-workers, they retrieved the data of the cryo EM structure of 2019-nCoV S-protein (PDB ID—6vsb) and X-Ray diffraction structure of ACE2 of host cell (PDB ID-1r42) with resolution of 3.46 A0 and 2.2 Å respectively from PDB database[22]. The FASTA sequence of S-protein of 2019-nCoV was also retrieved from PDB database and evolutionary analysis of genetic distance and diversity were conducted by

Fig 1: Structure of catechin and its der ivatives



Source Total Amount of Catechins (mg/100 g) Abundant Type

Apple 10–43 EGCG

Apricot 10–25 Epicatechins

Cherry 5–22 EGCG

Strawberry 2–50 Catechin

Beans 35–55

Lemon EGCG

Black tea 6–50 EGCG

Green tea 10–80 EGCG

Cider 4 Catechin

Red wine 8–30 Catechin

Green algae (Acetabularia ryukyuensis)

33.3, 500 ± 320 Catechin, epicatechin

Eisenia bicyclis 38.6 Catechin gallate, epicatechin

Red algae(Chondrococcushornemannii)

217 ± 95, 1600 ± 76 Catechin, epigallocatechin

Chocolate 46–61

Table 1: Major Sources of Catechins in Conventional and Nonconventional Foods [20]

MEGA-X. Analysis was accomplished using the Substitution Model Jones-Taylor-Thornton (JTT)[23] and standard error estimate(s) were obtained by a bootstrap procedure (1000 replicates). Further they carried out molecular docking of catechin with one of the structural proteins, S-protein or the spike protein of coronavirus. The binding properties of catechin with S-protein and ACE2 were studied through system AutodockVina1.1.2 Table 2. highlights the binding interactions of catechin with the spike protein of CoV-

Protein Ligand Binding Affinity Interaction AA: Name; Chain Name; AA: No;

S-protein Catechin -10.5 Vanderwaals

Gln B:314, Glu B:309, Lys B:310,Gly B:311, Ile B:664, Lys C:733, Leu C:861, Asp B:950, Gly C:769,Ala C:766, Lys B:304, Thr C:761

Hydrogen Bond

Gln B:314, Glu B:309, Lys B:310,Gly B:311, Ile B:664, Lys C:733, Leu C:861, Asp B:950, GlyC:769,Ala C:766, Lys B:304, Thr C:761

Carbon-Hydrogen Bond

Ile B:312

Pi- Sigma Thr C:768, ValC:772, Leu B:303

Pi-Cation Arg C:765

Pi-Alkyl Ile B:312, ProB:665, Arg C:765

Table 2: Molecular docking study of catechins with S-protein of CoV-2

2virus.

On December 6 2020, E. Ohgitani and his co-workers published the in vitro study regarding the potential effect of tea and their constituents on SARS-CoV-2 viruses. Theasinensin A (TSA), (-)epigallocatechin gallate (EGCG)and theaflavin 3,3’-di-gallate (TFDG) significantly inhibited interaction between recombinant ACE2 and RGD of S protein. These results strongly suggest that catechin and its derivatives inactivate the novel coronavirus and are



effective antiviral candidates. Further, he carried out cell viability analysis. It was observed that the cells pre-treated with Theasinensin A (TSA), (-)epigallocatechin gallate (EGCG)and theaflavin 3,3’-di-gallate (TFDG) were susceptible to virus when compared to non-treated cells. [24-28]

In another study, Catechin was found to effectively bind (range of 5.79 ̶ 8.36 kcal/mol) with five target proteins: RBD, Cathepsin L, nucleocapsid protein, 3CLpro and NSP-6of the coronavirus, thereby proving its potential as an anti-viral agent.[29]

Conclusion :

The Covid-19 virus has created a major impact on the social, health and economic systems of the whole world. The lethality of the virus has taken many people’s lives. There is urgency to control the widespread outbreak of this infection. Here, I tried to gather and highlight the information on polyphenols -catechins (antiviral) as potential candidates for CoV-19 inhibition. The potential of this promising molecule can be further exploited through rigorous in vitro studies to support its efficacy in treatment of the COVID-19 infection.

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Pharmaceutical Resonance 2021 Vol. 3 Issue 2 · 2021. 1. 7. · Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, 411018, Maharashtra, India Sonali