key: cord-0969175-zzly5j21
authors: Islam, Sk Saruk; Saadi, Sk Md Abu Imam
title: "Natural medicinal plant products as an immune-boosters: A possible role to lessen the impact of Covid-19"
date: 2021-05-05
journal: nan
DOI: 10.1016/j.cscee.2021.100105
sha: c5089a969ca356e56f5bd94290d3f177ffcc1793
doc_id: 969175
cord_uid: zzly5j21

Transmissible Covid-19, caused by novel corona virus since last of 2019 has outspread widely until now. Where, India was the second most affected country and 3rd in mortality rate. In world ancient history, medicinal plants were played a crucial role to cure several diseases. In present study, we show some novel natural medicinal plant metabolites as the potential inhibitors against papain-like protease (PLpro), main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), transmembrane proteinase Serine 2 (TMPRSS2) and angiotensin converting enzyme-2 (ACE-2) of Covid-19. Plant metabolites were having been proven to inhibit SARS-CoVs, which also actively walkable against Covid-19.

Coronavirus disease is an acute respiratory infectious disease caused by SARS-CoV-2 a novel coronavirus strain that has emerged a pandemic issue and greatly effects public health widely in 2019-20 Boopathi et al., 2020; Zhu et al.,2020) . First case of Covid -19 was initially reported in Wuhan capital of Hubei Province of China and then it spread widely in 215 countries (Elmezayen et al., 2020; . The World Health Organization (WHO) declared Covid-19 as a Public Health Emergency of International Concern in 30 th January (https://www.who.int/), (Mackenzie & Smith, 2020) . This disease spread has led to more than 108,153,741 affirmed cases and 2,381,295 passed away around the globe on 14 th February 2021, and India was the second most affected country (10,904,940 affirmed cases) and 3 rd position in deaths (1,55,642) cases (https://covid19. who.int/table) in 14 th February 2021. Still to date the number of affected cases in was steadily increasing across the globe, and so far, due to its high mortality rate and rapid transmission by human-to-human connection (WHO, 2020) (Aanouz et al., 2020; Zhu et al., 2020; Bhatraju et al., 2020) . After SARS-CoV in 2002 and MERS-CoV in 2012, Covid-19 ranked third disease epidemic situation in human population during 21 st century Yuan et al., 2020; Gupta et al., 2020) . are identified as β-coronavirus, enveloped, positive ss-RNA viruses with varied genome size ranging from 26-32 kilobase pairs and genome sequence similarity with MERS-CoV and SARS-CoV (Chan et al., 2020; Zhu et al., 2020) . Nomenclature of based on its 82% identity to the SARS-CoV genome sequence by the taxonomists Coronavirus Study Group (CSG) under the aegis of International Committee on Taxonomy of Viruses (ICTV) (Hasan et al., 2020) . In Indian subcontinent history, herbal medicinal plants were used to cure various diseases based on health healing systems. It was established that various medicinal plant such as: Angelica keiskei inhibit cysteine proteases of SARS-CoV (Park O. K. et al., 2016) , Ecklonia cava as a SARS-CoV 3CLpro inhibitor (Park et al. 2013) , Salvia miltiorrhiza effects on cardiovascular system during SARS-CoV (Park O. K. et al. 2012) , Torreya nucifera (L.) acts as a SARS-CoV 3CLpro inhibition (Ryu et al., 2010) , Isatis indigotica an Anti-SARS coronavirus 3C-like protease inhibitor (Lin et al., 2005) and Lycoris radiata have antiviral activities against SARS-associated coronavirus (Li et al. 2005) were used for disease cure through ayurveda treatments. It was reported that, different compounds extracted from medicinal plant like steroids, polysaccharides, alkaloids, glycosides, etc have anti-viral, anti-bacterial, anti-fungal, anti-inflammatory, analgesic, anti-diabetic, anti-stress, antitumourneuro protective, rejuvenating, cardioprotective and immunomodulatory effects in several disease (Kapoor, 1990; Sharma et al., 2011; Ven Murthy et al., 2010; Vyas et al., 2011; Jamshidi & Cohen, 2017) . From the beginning of Covid-19 outbreak in china, traditional herbal medicines were used to cure the viral disease. It was found that out of 214 Covid-19 patients, 90% of patients were recovery from the Covid-19 viral disease by using the traditional herbal medicines in China (Hong-Zhi et al., 2020; . Furthermore, to cure these viral diseases, specialists recommended different herbal medicinal plant for Covid-19 patients based on their disease-stage and symptom differentiation . In present review, we summarize the proposed plant derived metabolites to suppress the causative agent of i.e., severe acute respiratory syndrome coronavirus-2. Hence forward, we explored the effect of some plant metabolites like emodin, lopinavir, lycorine, oseltamivir, hypericin, etc against the Covid-19 disease. So, present review emphases on the probable uses of herbal medicinal plant metabolites and natural products to prevention or treatment of Covid-19 infection.

By effectively completing joint examination, the structure of encodes key proteases such as papain-like protease (PLpro), main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) have been established in Nature & Science. (Thiel et al., 2003) . These proteases are engaged with the proteolytic handling of the polyproteins into individual nonstructural proteins (nsps) to control the viral genome articulation and replication (Xue et al., 2008) . A started program of consolidated structure helped is utilized for drug plan, virtual medication screening and high throughput screening to recognize new medication drives that focus on the Covid-19 infection principal protease was planned. For this outbreaks situation to discover active compounds to suppress the causal microbes, scientists and researchers discover some inhibitor like N3, through docking-based drug designing process and subsequently design the structure of Covid-19 virus protease i.e., Mpro (3CLpro) interacted with that compound (Jin, Du, & Xu, 2020) . RdRp, (namely nsp12) is the focal segment of coronaviral transcription and replication apparatus and shows up. Specialists likewise report that cofactors nsp8 and nsp7 complex with the cryo-EM structure of Covid-19 infection full-length nsp12 at 2.9-Å resolution. A relative investigation model established how Remdesivir ties to that polymerase. The structure gives a premise to the plan of new antiviral therapeutics focusing on viral RdRp (Gao, Yan, & Huang, 2020) . The study only focuses on the antiviral potential of medicinal plants against human SARS coronaviruses since the pandemic by SARSCoV-2 has become the greatest catastrophe event in the 21 st century, and until now, there is no specific medication discovered to treat patients infected by this virus. Moreover, various important phytochemical groups, and their potentials for exhibiting human coronaviruses are discussed in details (Fig. 1 ).

The infiltration of the SARS-CoV-2 genome into the host cells happens because of the SARS-CoV-2 spike protein authoritative to have receptors (Sigrist et al., 2020) . Hoffmann et al. (2020) exhibited that the ACE2 receptor is utilized by SARS-CoV-2 to enter human cells. Study report that, 25 Chinese natural families were found to fundamentally restrain the communication SARS-CoV -ACE2. Among them, Polygonaceae, Labiatae, Magnoliaceae, and Nelumbonaceae displayed the main inhibitory impacts. These inhibitory impacts were credited to emodin (1,3,8-trihydroxy-6 methylanthraquinone) delivered in significant levels in variety Rheum and Polygonum. Emodin hindered the communication SARS-CoV S protein and ACE2 in a portion subordinate way with an IC50 of 200 μM (Ho et al., 2007) ( Table 1 ; Fig. 2 ).

Recently, Hoffmann et al. (2020) demonstrated that besides using ACE2 receptor arrive to the host cells, SARS-CoV-2 uses also TMPRSS2 for S protein priming. After the interaction among the S protein (SARS-CoV-2) and the ACE2 (host cell), the complex is cleaved by the TMPRSS2 to facilitate viral entry (Rabi et al., 2020) . Matsuyama et al. (2020) found that an significant TMPRSS2 expression in cells makes them extremely vulnerable to SARS-CoV-2. Several studies have demonstrated that natural products could down regulate or suppress TMPRSS2. It has been shown that kaempferol was able to inactivate TMPRSS2 expression by 49.14 and 79.48% at 5 and 15 mM, respectively (Da et al., 2019). Mamouni et al. (2018) found that a standardized flavonoids formulation including luteolin, quercetin, and kaempferol significantly suppressed TMPRSS2 expression (Table 1 ; Fig. 2 ). Main protease (Mpro) is a homodimer in nature with three structural domains as domain-I, II & III (Anand et al., 2002) . Also, the M-protease is extremely well-preserved among all the Corona viridae members like as MERS-CoV and SARS-CoV, exhibiting about 40-44% of sequence homology regions (Yang et al., 2003) . Protease enzymes are actively worked in proteolytic cleaves, where the M-protease generated the non-structural proteins i.e., nsps which actively play an important role in replication of viral genome (Zhao et al., 2013) . The substrate-restricting site is situated in the Cys-His synergist dyad situated in a separated between the domain I and II (Shi et al., 2004) . Researcher established that, dimerization of these two protomer is significant; notwithstanding, just a single protomer is dynamic at a time. Henceforth, M-protease has developed as the most important potential antiviral objective due to its primary part in self-development and ensuing development of polyproteins (Chen et al. 2006) . Previous study suggested that phenolic compounds (indigo, indirubin, sinigrin, beta sitosterol and aloeemodin) of Isatis indigotica blocks the viral J o u r n a l P r e -p r o o f cleavage processing and effects on 3C-like protease of anti-SARS coronavirus (Lin CW et al. 2005) . Successfully inhibition of Covid-19 by combination molecular docking of the oseltamivir, ritonavir and lopinavir were supremely active against SARSCoV-2 protease protein Nisha Muralidharan et al., 2020) . Thus, broad in silico contemplates were performed to recognize potential medication competitors, for instance, Bictegravir, Prulifloxacin, Tegobuvi, and Nelfinavir were distinguished as repurposing up-and-comers against Covid-19 by searching for drugs with high restricting limit with SARS-CoV primary protease . Once more, Nelfinavir, a HIV-1 protease inhibitor was likewise anticipated to be an expected inhibitor of Covid-19 fundamental protease by another computational-based investigation (Miller JS et al. 2001) (Table 1 ; Fig. 2 ).

Covid virus are RNA viruses which multiply and replicates in host cells. In the viral genome replication process, RNA-dependent RNA polymerase (RdRp) enzyme plays an important role for synthesis both negative and positive-strand RNA of viral genome. (Gao et al., 2020) . After replication of genomic material, it gone to the maturation phase of virus genome in the host cell using of proteases alike enzyme like as Papain-like protease (PLpro) and 3C-like protease (3CLpro) (Elmezayen et al., 2020) . Utilizing swine testicular (ST) cells, plantinferred poisonous substances, as cardenolides (steroid) were applied to watch the movement of hostile to contagious gastroenteritis Covid (TGEV) action . The outcome indicated that ouabain, a significant cardenolide, diminished the amount of TGEV in a given volume of liquid at 0-3000 nM. At the inhibitory centralizations of ouabain (37 nM and 23 nM), the quantity of viral RNA duplicates was likewise decreased to half because of the concealment of viral replication and TGEV action, which at long last lessened viral yield . A few medications are known to have the option to restrain these three cycles, including camostat mesylate as TMPRSS2 inhibitors, arbidol as ACE2 inhibitors, ritonavir and Lopinavir as protease inhibitors, ribavirin and remdesivir as RdRp inhibitors. Previous publication established that, Ritonavir, Chloroquine, Remdesivir, and Lopinavir are an antimicrobial that noticeable has a prospective action in contradiction of (Wu C, et al., 2020 . Now, in silico analysis also revealed that polyphenols compounds can inhibit RdRp effectively (Abdelmageed MI et al, 2020 , Ghosh R, 2020 (Table 1 ; Fig. 2 ).

Covid-19 induces unadorned breathing disorder in humans' beings [Shen M, 2020] . Major proteins of this viral include nucleocapsid protein (N), matrix protein (M), small envelope protein (E) and spike protein(S) [Fields BN et al 2001] . The position of viral add-on to the host cell membrane is within the Spike protein. On average 74 surface spike protein have in coronavirus particle (Neuman BW 2011) . The Covid-19 S-protein attach to the host cell membrane by a receptor-mediated communication which allows the virous entrance in to the host cell. Researcher established by computationally gritty that, SARS-CoV-2 has alike mechanism like as SARS virus and strongly binds to the angiotensin-converting enzyme-2 (ACE2) receptor [Donald C. et al. 2020; Zhou P, et al., 2020] . For attachment, the S protein receptor binding domain (RBD) of SARS coronaviruses in human beings interact with hACE2 receptor binding motif, which existing in the human lungs outer cell membrane (Letko et al., 2020) . It has proposed that diminishing the degrees of ACE2 on the cell surface or hindering its capacity, helps in forestalling SARS-CoV-2 contamination [Yan R, et al., 2020 , Donald C. et al.2020 . This association will initiation conformational changes of S2 subunit in C-terminal (liable for infection cell film combination) of the S-protein (Benarba B et al. 2020) . By restricting the S-protein to the ACE2, the angiotensin 2 is delivered in enormous amounts by the ACE and afterward ties to the AT1R receptor. This cycle prompts fibrosis and harmful for lung tissues. A potential method of battling the contamination could be the infusion of solvent ACE2 into the circulation system which will have the two-overlay impact; forestalling the connection of the infection to non-tainted cells and renewing ACE2 in contaminated cells. Furthermore, we targeted three different spike protein domains of SARS-CoV-2, where all of these are play crucial roles to manage the viral entry into the host cell [Shang J et al 2020] . Furthermore, docking lessons and MD may likewise be utilized to focus on the Covid S-protein to keep it from entering ACE2 have cells. Cleavage of S-protein of Covid by protease factor Xa is related with viral infectivity (Du, L., et al. 2007 ). The immunization named mRNA-1273 which contain hereditary material from the S-protein in SARS-CoV-2 and typified with a lipid nanomaterial. In any case, the investigation of appropriate secure immunization is as of now under assessment and results are yet to be out (Yengkhom Disco Singh. 2020) ( Table 1 ; Fig. 2 ).

Researcher established that different protease i.e., papain-like protease (PLpro), main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) are actively work in viral nucleic acid replication and maturation of Covid-19. Therefore, these proteases are play a crucial role for viral multiplication, which cleaves the viral polyproteins such as PP1A and PP1AB into effector proteins (Jiang et al., 2020) . These proteases are blocks by some traditional medicinal plant derived product, here some important medicinal products are listed below ( Fig. 3A and 3B ). Previous study supports that Ethanolic extract of some plant species like Psoralea corylifolia and Cullen corylifolium showed important inhibitory function on PLpro an IC50 of 15 μg/ml. of SARS-CoV. Additionally, some flavonoids compounds present in extract such as Bavachinin, corylifol A, isobavachalcone and psoralidin were inhibit the function of PLpro of SARS-CoV through a dose dependent way with IC50 predictable to be 1.2 to 38.4 μM. Psoralidin showed highest inhibitory effects (IC50 value 4.2 ±1.0 μM) and isobavachalcone (IC50 value 7.3 ± 0.8 μM) .

Paulownia tomentosa is a high source of miscellaneous secondary metabolites products, mostly prenylated flavonoids compounds. As of today 135, compounds such as flavonoids, glycosides, glycerides, lignans, phenolic quinones, phenolic acids, terpenoids, and other miscellaneous compounds have been isolated from various extracts of this plant. In P. tomentosa fruit, five tomentin bioactive compounds such as tomentin A, tomentin B, tomentin C, tomentin D and tomentin E were found till now. An in vitro study to know the efficacy of tomentin bioactive components extracted from P. tomentosa fruit, against SARS-CoVs disease were done by Cho et al., In 2013. These tomentin components has the ability to inhibit SARS-CoV PLpro activity in a dose dependent way with an IC50 value of 5.0 to 14.4 µM. Tomentin E showed the most elevated inhibitory impact with an IC50 of 5.0 ± 0.06 μM (Siddiqui, A.J et al 2020).

3.3. Angelica keiskei (Miq) Koidz. Park et al. (2016) explored the repressive potential of various alkylated chalcones compounds such as isobavachalcone, xanthoangelol-A, xanthoangelol-B, xanthoangelol-D, xanthoangelol-E, xanthoangelol-F and xanthoangelol-G, and four coumarins were extracted from Angelica keiskei ethanolic extract. These chalcones can inhibited PLpro of SARS-CoV viral disease in a varied range of significant dose-dependent way, where the IC50 values ranging from 1.2 ± 0.4 to 46.4 ± 7.8 μM.

Salvia miltiorrhiza ethanolic extract (30 μg/ml) triggered 88% embarrassment of SARS-CoV PLpro gene. Moreover, some bioactive compounds of tanshinones such as rosmariquinone, methyl tanshinonate, tanshinone I, cryptotanshinone, anshinone IIA and IIB) were recognized from the n-hexane element. Fluorometric assay state that these bioactive tanshinones were assessed with esteem to inhibition of PLpro gene of SARS-CoV virus. These molecules exhibited important inhibitory time-dependent activities with IC50 of 0.8 to 30 μM. ).

Park et al. (2012b) utilized movement guided fractionation to distinguish nine diarylheptanoids (oregonin, platyphyllenone, rubranoside B, hirsutenone, platyphyllone, hirsutanonol, rubranol, platyphyllonol-5-xylopyranoside and rubranoside A) from the ethanol concentrate of Alnus japonica. They assessed their SARS-CoV PLpro inhibitory impact utilizing a consistent fluorometric test. The outcomes demonstrated that hirsutanonol, hirsutenone, oregonin, rubranoside B, rubranol and rubranoside. An applied a critical portion subordinate inhibitory movement towards SARS-CoV PLpro with IC50 going from 3 to 44.5 μM. Hirsutenone had the most intense inhibitory impact with IC50 of 4.1 ± 0.3 μM which was less significant than that of the reference inhibitor curcumin (5.7 μM).

3.6. Scutettaria baicalensis Georg and Aglaia perviridis Hiern 64 regular atoms began from 15 restorative species were assessed with respect to their inhibitory action of SARS-CoV helicase. Myricetin and scutellarein altogether hindered the SARS-CoV helicase movement. At 10 μM, myricetin (IC50 = 2.71 ± 0.19 μM) and scutellarein (IC50 = 0.86 ± 0.48 μM) had the option to repress 90% of the ATPase action of the SARS-CoV helicase. As needs be, Myricetin and scutellarein were recommended to be promising future enemy of SARS drugs.

Angelica keiskei (Miq.) Koidz. (Family-Apiaceae) has usually been used to treat dysgalactia, dysuria, and dyschezia as well as to restore vitality. It was established that nine nine alkylated chalcones, four coumarins, acetylenes, diterpene, various flavonoids, phenolics, sesquiterpene and triterpenes were isolated as the constituents of A. keiskei. Inhibitory potential efficacy of nine alkylated chalcones and four coumarins against SARS-CoV protease (3CLpro and PLpro) were determined. Isolated chalcone 6, alkylated chalcones, containing the perhydroxyl group, showed the highly potent SARS-CoV protease (3CLpro and PLpro) inhibitory activity with the IC50 values of 1.2 and 11.4 μM. The activity of these chalkones components ranged from the IC50 11.4 ± 1.4 to 129.8 ± 10.3 μM. Additionally, xanthoangelol E was likewise found to repress SARS-CoV-PLpro J o u r n a l P r e -p r o o f (Park O. K. et al., 2016) it very well may be a promising up-and-comer in the remedial methodology against Covid-19.

3.8. Ecklonia cava (Algae) Park et al. (2013) detached nine phlorotannins from the ethanolic concentrate of earthy colored Alga Ecklonia cava. These phlorotannins were surveyed with respect to their inhibitory impacts towards SARS-CoV-3C (ace) utilizing a without cell-based test. Some phlorotannins (triphloretol A, 2-phloroeckol, 7-phloroeckol, fucodiphloroethol G, dieckol, and phlorofucofuroeckol A) were demonstrated to be serious inhibitors of SARS-CoV-3CL (expert) in a portion subordinate way. IC50 ranged varied from 2.7 ± 0.6 (dieckol) to 164.7 ± 10.8 μM (triphloretol A).

Park O. K. et al. (2012) investigated the inhibitory potential of Salvia miltiorrhiza towards SARS-CoV-3CL (pro). They found that Salvia miltiorrhiza ethanolic extract (30 μg/ml) resulted in 60% inhibition of SARS-CoV-3CL (pro). Furthermore, they demonstrated that six tanshinones of the plant (lipophilic fraction) exerted marked inhibition of SARS-CoV-3CL (pro) in a dose-but not-time-dependent manner. IC50 was estimated at 14.4-89.1 μM. Dihydrotanshinone I showed the utmost significant repressive outcome with an IC50 of 14.4 ± 0.7 μM..

Four biflavonoids compounds such as sciadopitysin, ginkgetin, amentoflavone and bilobetin were extracted from the leaves of Torreya nucifera also evaluated their inhibitory function on SARS-CoV-3CL (pro) by FRET. All biflavonoids compounds were showed an obvious inhibitory action on SARS-CoV-3CL (pro) gene with IC50 of 8.3-72.3 μM. These repressive actions were showed highly stronger than that of some other eight diterpenoids compounds extracted from the T. nucifera (IC50: 49.6-283.5 μM). Amentoflavone applied the main inhibitory action since it had the least IC50 (8.3 ± 1.2 μM). In addition, its inhibitory potential was a higher priority than that of apigenin. (IC50 = 280.8 ± 21.4 μM), quercetin (IC50 = 23.8 ± 1.9 μM) and luteolin (IC50 = 20.0 ± 2.2 μM) (Ryu et al., 2010) .

Various plant-based phenolic compounds and isolated 5 major secondary metabolites from root extract of Isatis indigotica were acts as potential antiviral against human corona viruses; in which, β-sitosterol, hesperetin, aloe emodin, indigo, & sinigrin were the significant phytochemicals that inhabited the cleavage activity of SARS 3CLpro enzyme with IC50 values of 1210, 365, 8.3, 752, and 217 μM, respectively (Lin et al., 2005) .

3.12. Lycoris radiata (L'Her.) Herb:

According to Li et al. (2005) ethanol/chloroform extracts of Chinese medicinal herbs produce a single compound (lycorine) from one plant species L. radiata was earmarked as a potential drug candidate against SARS-CoV. Lycorine showed the quite higher antiviral efficacy, where the EC50 is 15.7±1.2 nM.

J o u r n a l P r e -p r o o f

The ongoing status of covid-19 is a big issue in the world for the human beings. As we know that, there is no antiviral medicines are available in the market which play the important role to cure the covid-19 patient. The only one-way hope for the present situation is to rely on bioactive molecules from natural products as they have antiviral properties against the covid-19. Researchers are trying to discover the highly effective antiviral compounds to combat covid-19. Medicinal plants and natural plant products are still considered promising substitutes to cure and prevent various diseases. In present situation, our study emphasized some plant derived secondary metabolite compounds that showed actively antiviral properties against coronaviruses through impeding the main machinery used in their pathogenesis and replication cycle. But the lessons assessing the anti-Covid-19 effects of traditional medicinal metabolites are still inadequate and comparatively undeveloped so, there is a crucial necessity to recognize and develop active antivirals in contradiction of Covid-19 to fight it. Present review reveals that some natural medicinal products with IC 50 value ranging from 0.8 to 46.4 µM and above may well be considered as auspicious anti-Covid-19 agents, also these have capability to block some important proteins i.e., papain-like protease (PLpro), main protease (Mpro), cellular receptor ACE2 and RNA-dependent RNA polymerase (RdRp). Some interventional studies are still required to prevent, assessed the Covid -19 viral infection with suitable plant metabolites or natural herbal medicinal plant products.

Author's contribution: All authors are equivalently effort to prepare the manuscript.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors Declaration of competing interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Guo, Y.R., Cao, Q.D., Hong, Z.S., Tan, Y.Y., Chen, S.D., Jin, H.J., Tan, K.S., Wang, D.Y., Yan, Y., (2020) 

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None.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.J o u r n a l P r e -p r o o f

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J o u r n a l P r e -p r o o f