key: cord-0817374-niwezca6 authors: Bhattacharya, Riya; Dev, Kamal; Sourirajan, Anuradha title: Antiviral activity of bioactive phytocompounds against coronavirus: An update date: 2021-01-23 journal: J Virol Methods DOI: 10.1016/j.jviromet.2021.114070 sha: d7b39a23b37e54bfbdef4e49a6ba5b134203b556 doc_id: 817374 cord_uid: niwezca6 Viral infections are one of the main cause of diseases worldwide due to the rising trends of migration, urbanization and global mobility of humans. The outbreak of corona virus diseases caused by SARS-CoV (year 2003), MERS-CoV (year 2012) and SARS-CoV-2 (year 2019) raised global health concerns. The side effects associated with the conventional drugs and increase in cases of anti-microbial resistance have led the researchers to switch to natural sources, especially plants, as they have immense potential to be used as antiviral agents. The aim of the article is to summarize the evidences of the bioactive phytocompounds from different plants as an effective alternative for the treatment of infections caused by coronaviruses. However, the use of most plant compounds succumbs to limitations due to lack of experimental evidences and safety studies. Therefore, further research and studies are required to validate their therapeutic uses for wide application of plant-based medicine, including anti-virals. to the nucleotide changes in the spike (S) protein and its receptor-binding domain (RBD) (Kannan et al., 2020 , Coutard et al., 2020 , Wan et al., 2020 . Therefore, scientists worldwide are exploring the preventive methods and treatment for COVID-19, until a vaccine will be available (Balachandar et al., 2020) . As the world is awaiting curative remedies for COVID-19, there have been several attempts in the recent past towards repositioning of existing drugs to combat the spread of COVID-19. The World Health Organization (WHO) estimates that about 80 % of global population rely on traditional medicine to treat infectious diseases (Pan et al., 2013) . Several in vitro and in vivo studies carried out on plants and their derived products have helped to develop effective antibiotic, antimitotic, and antiviral activities. In addition, the pharmaceutical companies began to develop new antimicrobial drugs from natural plant sources (Barreca et al., 2017) . The evaluation of several medicinal plants revealed their potential to be used as therapeutic agents against different viruses (Akram et al., 2018) . The available antiviral drugs act on specific enzymes involved in targeting the viral structure or in the replication cycle, making them effective targets. But the failure of several conventional drugs against viral infections and the rise in incidence of specific viral resistance has led to an interest in plants as an alternative source of effective antiviral agents (Irwin et al., 2016) . Different plant components including essential oils and phytocompounds, such as phenolic acids, flavonoids, terpenes, lignans, coumarins, and alkaloids exhibit potential activity against viruses (Daglia et al., 2012) . Thus, medicinal plants are a promising source for treatment viral diseases (Gomathi et al., 2020) . With the onset of COVID-19 pandemic, research has been initiated to screen the potential of several plant secondary metabolites in inhibiting the SARS-CoV-2 main protease (M pro )/chymotrypsin-like protease (3CL pro ) using molecular docking analysis to examine binding affinity. However, screening a large number of medicinal plants for phytocompounds with antiviral activity against SARS-CoV-2 will be a challenge in very short period of time. Drug discovery is a time consuming, slow and challenging process (Shaikh et al., 2013 , Eweas et al., 2014 . Thus, it is necessary to exploit computational tools for new drug development, which has made the process of drug discovery rapid and cost effective in the past (Eweas et al., 2014) . For screening and searching phytocompounds, the ligand-based virtual screening tool/ molecular docking is very effective to identify most probable molecule with pharmacological activity (Guo et al., 2014 , Banegas et al., 2018 . The aim of this review is to provide an update on the antiviral activity of different medicinal plants and their isolated bioactive phytocompounds, their mechanism of action and potential interactions with conventional drugs. The review focuses on the literature available on structure, immunological influence, mechanism of action of the phytocompounds, ongoing clinical trials, recent diagnostics and the potential use of certain medicinal herbs for the effective treatment of coronavirus. Based on the review of literature, we suggest that the traditional medicinal plants can be used as a beneficial and effective means to combat viruses like the SARS-CoV-1, MERS-CoV and SARS-CoV-2. There are total 39 species of coronaviruses under the realm of Riboviria, which belong to the family Coronaviridae, suborder Cornidovirineae and order Nidovirales (Gorbalenya et al., 2020) . All the SARS-CoV viruses fall under the species severe acute respiratory syndrome-related coronavirus and genus Beta-coronavirus. Most of the species are enzootic and only few species infect humans (Schoeman et al., 2019) . So far, seven human CoVs (HCoVs) have been reported, which include, human coronavirus NL63 (HCoV-NL63) and human coronavirus 229E (HCoV-229E) of the alpha-coronavirus genus, and human coronavirus OC43 (HCoV-OC43), human coronavirus (HCoV-HKU1), SARS-CoV, SARS-CoV-2 and middle east respiratory syndrome coronavirus (MERS-CoV) of the beta-coronavirus genus. Human coronaviruses are mostly associated with upper respiratory tract infection, which ranges from mild to moderate, including common cold. It is believed that most of the people might have been infected with one of these viruses at some point in their lifetime (Killerby et al., 2018) . The SARS-CoV and MERS-CoV are the two major viruses that are responsible for severe pneumonia in humans . The emergence of SARS-CoV was first reported in The genome of SARS-CoV encodes the structural spike (S) glycoprotein, membrane (M) glycoprotein, small envelope (E) protein and nucleocapsid (N) protein in 5ʹ-3ʹ direction within the 3ʹ proximal 1/3 rd region of the genome. All the SARS-CoV genomes harbor an extremely large gene 1 (separated into ORFs 1a and 1b and extending over two-thirds of the genome) encoding nonstructural proteins responsible for proteolytic processing of the gene 1 polyprotein products, virus genome replication, and sub-genomic (sg) mRNA synthesis (Fig 1) . A variable number of ORFs appearing to be virus-or group-specific, encoding nonstructural proteins (nsps) are also present in the genome. These include ORF 3a (7.7 kDa protein), ORF 3b ( , ORF 4a (4.9 kDa protein), ORF 4b (4.8 kDa protein), ORF 5 (12.7 kDa protein), and an ORF internal to gene 7 (23 kDa I protein) in BCoV (Bovine coronavirus); and ORF 3a (6.7 kDa protein), ORF 3b (7.4 kDa protein), ORF 5a (7.5 kDa protein), and ORF 5b (9.5 kDa protein) in IBV (Avian coronavirus) (Fig. 1) . The 5'-untranslated region (UTRs) ranges in length from 209 to 528 nt and contains a similarly positioned short, AUG-initiated open reading frame (ORF) relative to the 5ʹ end (Morris et al., 2000) . The 3ʹ UTRs vary in length from 288 to 506 nt, with some strains of IBV having 3' UTRs of greater length because of internal sequence duplications (Williams et al., 1993 . They possess an octameric sequence of GGAAGAGC upstream of the 3ʹ-terminal poly(A) tail. The genome of MERS-CoV strain was reported to be 30,114 nucleotides (nt), including the 3ʹ and 5ʹ UTRs. The MERS-CoV exhibits structural genomic organization of betacoronavirus with the following components: 5ʹ-untranslated region (UTR) (nt 1 to 272), replicase complex ORF1ab (nt 273 to 21508), S gene (nt 21450 to 25511), ORF3 (nt 25526 to 25837), ORF4a (nt 25846 to 26175), ORF4b (nt 26087 to 26827), ORF5 (nt26834 to 27508), E gene (nt 27584 to 27832), M gene (nt J o u r n a l P r e -p r o o f 27847 to 28506), N gene (nt 28560 to 29801), ORF8b (nt 28756 to 29094), and 3ʹ UTR (nt 29094 to 30114) (Fig 2) . The two essential poly-proteins namely pp1ab and pp1a are cleaved into 15/16 non-structural proteins (nsp) by 3CL pro and PL pro . The nsps include nsp12, nsp13, nsp14, nsp15, and nsp16. The nsp14 protein functions as proofreading enzyme, thereby curtailing the mutation rates during replication of the genomic RNA of coronavirus (Ziebuhr et al., 2000 , Snijder et al., 2003 , Gorbalenya et al., 2006 , Smith et al., 2013 , Raj et al., 2014 , Durai et al., 2015 . Studies have revealed that the accessory ORF proteins play an important role in MERS-CoV infection and pathogenesis (Menachery et al., 2017) . The MERS-CoV has the potential to adjust and survive in new environments by acquiring various virulence factors and their transfer from one person to other during outbreak (Zumla et al., 2015) . The phylogenetic analysis revealed that human and camel MERS-CoV were homologous to each other. SARS-CoV-2 are spherical positive single-stranded RNA viruses that are identified by the presence of S proteins projecting from the virion surface (Fig 3) (Neuman et al., 2006 , Barcena et al., 2009 ). The spherical shape of SARS-CoV-2 along with the spike projections led to the name coronavirus from the Latin word "corona" which means "crown", because of the appearance of the virus as a royal crown under the electron microscope (Neuman et al., 2006 , Barcena et al., 2009 ). Recent studies have demonstrated that SARS-CoV-2 has a similar genomic organization to other beta-coronaviruses, containing 5' UTR (265 nt), gene encoding a replicase complex (orf1ab), genes encoding non-structural proteins (nsps), S protein gene, E protein gene, M protein gene, N protein gene, 3'-UTR (229 nt), and other non-structural ORFs (Fig 3) . The S, ORF3a, E, M, and N genes of SARS-CoV-2 comprise 3822, 828, 228, 669, and 1260 nucleotides, respectively (Fig 3) . Similar to SARS-CoV, SARS-CoV-2 carries a predicted ORF8 gene (366 nt in length) found between the M and N ORF genes . However, SARS-CoV-2 is more diverse from MERS-CoV and SARS-CoV. Recent studies highlighted that SARS-CoV-2 genes share < 80 % nucleotide identity and 89.10 % nucleotide homology with their corresponding genes of SARS-CoV (Zhou et al., 2020 . The S, M, and E proteins are located in the viral envelope but the N protein interacts with the viral RNA and is present in the core of the viral particle, forming the nucleocapsid (Fehr et al., 2015) . The S protein is a glycosylated protein that is responsible for homotrimeric spikes on the surface of the viral particle and mediates viral entry into host (Bosch et al., 2003) . S protein exists as two subunits (S1 and S2) on the viral particle due to cleavage of S protein by host furin-like proteases during viral replication (Bosch et al., 2003 , Izaguirre et al., 2019 . The N protein binds with the viral RNA and is involved in packaging of viral RNA into the viral particle during viral assembly (Chang et al., 2006 , Hurst et al., 2009 . The M protein is one of the most important proteins in the virion structure. It is present in higher quantities than any other protein in the viral particle, while E protein is found in small quantities within the virion (Nal et al., 2005) . Although the source of transmission of SARS-CoV-2 is as yet unclear, it is believed that humans were infected through an unidentified intermediary animal host (possibly bats) followed by intense and rapid spread from human-to humans (Fig 3 and 4) . It is also believed that animals such as dogs, pigs might have served as intermediate host for SARS-CoV-2 (Fig 4) . In the advanced stages, the SARS-CoV-2 virus manifests the symptoms of pneumonia in the patients, which progresses to acute respiratory distress syndrome (ARDS), resulting in the need for life-support to sustain the patient's life (Gatera et al., 2020) . The current pandemic caused by SARS-CoV-2 is maintaining a sustained progression throughout the world, thus calling for an emergency international alarm for finding an effective cure and vaccine for this infection. During SARS-CoV and MERS-CoV outbreaks, diagnostic tools were developed for their accurate detection but they are not effective for detection of SARS-CoV-2. The nucleic acid detection of the viral particle is primarily used in SARS-CoV-2 diagnosis (Wang et al., 2020a (Wang et al., , 2020b (Wang et al., , 2020c . The collection of upper respiratory nasopharyngeal (NP) swabs for the diagnostic tests has been recommended (CDC, 2020). The Charité algorithm has two steps: the first step involves two reverse transcriptase PCR (RT-PCR) assays for genes encoding E protein and RNA-dependent RNA polymerase (RdRp) of Sarbecovirus subfamily; if both the tests are positive, the sample proceeds to the second step, wherein it is tested for SARS-CoV-2 specific RdRp by RT-PCR (Loeffelholz et al., 2020) . However, these methods are cost-intensive, and thus cheaper alternatives have been developed to track the symptoms of COVID-19 such as smart-phone surveillance J o u r n a l P r e -p r o o f (Dorigatti et al., 2020) . Imaging techniques are also used as a diagnostic method in COVID-19, including chest CT scans, which have been commonly used to detect lung abnormalities caused by SARS-CoV-2 infection (Shi et al., 2020 , Xu et al., 2020a , 2020b . The strategies used to halt the propagation of RNA viruses in host cells or tissues include inhibition of RNA transcription, RNA modification, virus packaging enzymes, and the capsid or surface proteins assisting the viral diffusion into the host cells (Dinesh et al., 2020) . The current treatment regimen for COVID-19 includes drugs such as remdesivir, chloroquine, arbidol, favipiravir, antiinflammatory drugs, anti-HIV drugs, and approaches such as interferon therapy, and monoclonal antibodies (Dinesh et al., 2020 , Dong et al., 2020 . However, there are no specific and completely effective medications against SARS-CoV-2. Although vaccine development against SARS-CoV-2 has been initiated, they are not available yet at the global level. Therefore, researchers are exploring the pool of natural and chemicals compounds that could inhibit the major proteases of the virus or downregulate the rate of propagation of the SARS-CoV-2 virus in the cells. Clinical trials are underway for major drugs that have the potential to treat COVID-19. Research on traditional medicine is also being undertaken to utilize them in the treatment of COVID-19. Plants provide a natural source of anti-viral inhibitors that can be extended for treatment of diseases caused by SARS-CoV-2. Hence, by repurposing the compounds and extracts from medicinal plants, more innovative and effective drug options can be unveiled for eliminating this viral transmission. The Earth is a hub of more than 5,00,000 plant species, of which 10 % are utilized as food source and 10-15 % as source of drugs (Borris et al., 1996) . Since ancient times, phytomedicine of ethnic communities used to be the basic method of treatment in China (Chang et al., 2014) , India (Dev et J o u r n a l P r e -p r o o f al., 1999), Africa and many other countries (Schultes et al., 1990) . Globally, a major proportion of the world's populations rely on plant-based medications for primary health care and phytocompounds as ingredients of drugs (Farnsworth et al., 1990) . Plants can serve as a wide source of viral protein inhibitors for the treatment of SARS. Plants produce a wide array of secondary metabolites that can possess inhibitory effect on the enzymes, proteins and the propagation of viruses. Secondary metabolites are expressed in response to biotic and abiotic stresses. Some examples include plant active compounds such as flavonoids, carotenoids, and diarylheptanoids. Over centuries, medicinal herbs have been used as a treatment and preventive strategy for several diseases, including respiratory viral infections (Park et al., 2016 , Kiran et al., 2020 , ul Qamar et al., 2020 . The benefit of using these herbs in viral respiratory infections is due to their immune stimulating and inflammation modulating effects to manage the immune system. Although numerous studies have focused on the SARS-CoV and MERS-CoV, there are few studies on cure for COVID-19 disease, which are limited to in silico studies of the phytocompounds (Mohammadi et al., 2020 , ul Qamar et al., 2020 . Natural medicine is a valuable field of research to extract and establish curative properties. However, limited number of phytochemicals have been systematically reported for their therapeutic potential (De Clercq et al.,2005 , Hostettmann et al., 2000 . The antiviral properties of phytocompounds on SARS-CoV, MERS-CoV and SARS-CoV-2 are summarized below (Table 1) : Glycyrrhizin, a bioactive compound of Chinese liquorice (Glycyrrhiza uralensis Fisch), and lycorine isolated from Lycoris radiata L. showed strong anti-SARS-CoV activity (Li et al., 2005) . Subsequently, Fiore et al (2008) extracted glycyrrhizin from Glycyrrhiza glabra and reported that glycyrrhizin is a potent inhibitor of SARS-CoV virus replication, and adsorption and penetration of virus during the early steps of the replicative cycle. The caffeine beverages like green and black tea from Camellia sinensis have bioflavonoids with several medicinal properties. A study reported that water soluble tannic acid and theaflavin-3 ,3ʹdigallate inhibit 3CL pro protease of SARS-CoV . Similarly, the phytocompounds J o u r n a l P r e -p r o o f namely hesperetin, sinigrin, beta-sitosterol, indigo and aloe emodin extracted from Isatis indigotica were found to have an inhibitory effect on the SARS-CoV 3CL pro . Quercetin is a flavonoid that is abundant in several plants and food products with a multitude of medicinal and pharmacological properties (Massi et al., 2017) . Both quercetin and quercetin 3-βgalactoside possess the ability to inhibit the activity of 3CL pro protease of SARS-CoV in vitro (Chen et al., 2006) . Wen et al. (2007) screened 221 phytocompounds isolated from Chamaecyparis obtuse, Juniperus formosana and Cryptomeria japonica against SARS-CoV and found that certain abietane type diterpenoids and lignoids have best anti-viral effects. Similarly, bioactive compounds isolated from six herbal extracts namely, Gentiana scabra (dried rhizome), Dioscorea batatas (tuber), Cassia tora (dried seed), Taxillus chinensis (leaf), and Cibotium barometz (dried rhizome) exhibited anti- and 200 μg/ml (Wen et al., 2011) . Several independent studies have shown that the compounds such as curcumin, caffeic acid, chalcones, cinnamic acid and betulinic acid isolated from different medicinal plants are potent inhibitors of 3CL pro protease of SARS-CoV (Table 1) Urtica dioica (Stinging nettle) has been used in different countries as traditional medicine for years owing to its therapeutic effects on cardiovascular, immune, nervous and digestive systems (Dhouibi et al., 2020) . Interestingly, lectins extracted from Nicotiana tabacum (tobacco agglutinin; NICTABA), Nicotiana benthamiana, and Urtica dioica exhibit strong inhibitory potential against proliferation of the SARS-CoV (Keyaerts et al., 2007 , Zheng et al., 2009 , Demurtas et al., 2016 . Li et al. (2005) showed that extracts of Lycoris radiata possess anti-SARS-CoV activity with a significantly lower dose of effectiveness (about 2.1 to 2.4 ug/ml). The antiviral activity of the extracts was attributed to the presence of lycorine in L. radiata (Li et al., 2005) . Phytocompounds targeting the second major protease PL pro include flavonoids (tomentins) from Paulownia tomentosa (Cho et al., 2013) , chalcones from Angelica keiskei (Park et al., 2016) , and diarylheptanoids extracted from Alnus japonica (Park et al., 2012) , which were reported as potent inhibitors of PL pro of SARS-CoV (Fig. 5 ). An alternative way to block the activity of the SARS-CoV is to target the spike protein (S) of SARS-CoV S proteins or blocking the human ACE2 receptor. Yi et al. (2004) reported that tetra-O-galloyl β-d-glucose from Galla chinensis and luteolin from Veronica linariifolia exhibit strong binding affinity to spike (S) protein of SARS-CoV. Emodin (1,3,8-trihydroxy-6methylanthraquinone), rhein (1,8-dihydroxy-3-carboxyl-9,10-anthraquinone), and chrysin (5,7dihydroxyflavone) are produced in high levels in plants of genus Rheum and Polygonum; these compounds were responsible for blocking the binding of S protein in SARS-CoV to ACE2 (Ho et al., 2007; Fig. 5) . Emodin blocked the binding of S protein to ACE2 in a dose-dependent manner (Ho et al., 2007) . Owing to the recent occurrence of COVID-19 pandemic and advances in virtual tools and databases available for drug screening, several research groups worldwide have reported in silico screening of phytocompounds reported for activity against SARS-CoV and other viral diseases. Zingiber officinale (ginger) is an herbaceous plant native to South Asia belonging to the Zingiberaceae family and has been used in various countries as traditional medicine for years. The phytocompounds of ginger have been screened for binding the proteins of SARS-CoV-2 (Rathinavel et al., 2020) . The phytocompound 6-gingerol showed the highest binding affinity (-15 .7591 kJ/mol) with 5R7Y SARS-CoV-2 main protease, which is essential for replication and propagation of SARS-CoV-2 (Rathinavel et al., 2020) . Moreover, 6-gingerol possesses excellent drug likeliness with zero violations and very good pharmacokinetic properties, indicating its potential for treating COVID-19. Organosulfur compounds are found in the plants of the Allium genus such as onions (e.g. Allium cepa), and garlic (Allium sativum). In a recent in silico study, the organosulfur materials such as allyl disulfide and allyl trisulfide from Allium sativum showed significant potential in binding to human ACE2, the target of SARS-CoV-2 (Thuy et al., 2020). In another study ul Qamar et al. (2020) screened the Chinese medicinal plants library of 32,297 phytocompounds for potential binding with 3CL pro of SARS-CoV-2 generated by homology modeling. The isoflavone namely 5,7,3′,4′-tetrahydroxy-2'-(3,3-dimethylallyl) isoflavone extracted from Psorothamnus arborescens showed the highest binding affinity with 3CL pro of SARS-CoV-2 (Table 1; ul Qamar et al., 2020) . Table 1 ). Most of these compounds have been used for treating other ailments in humans, revealing their multi-dimensional pharmacological properties. Analysis of the targets and mechanism of action of the phytocompounds indicates a broad spectrum of J o u r n a l P r e -p r o o f targets on both coronaviruses and the host receptors (Fig. 5) . These include blocking of ACE2 receptor binding by spike protein, inhibition of viral proteases, inhibition of viral replication, targeting coronavirus spike protein, and blocking viral entry into host ( Fig. 5; Table 1 ). With ongoing research for COVID-19 therapeutics, the list of anti-viral phytocompounds is certainly dynamic with more anticipated updates. Over the past few decades, there has been a huge demand to decipher the root of coronavirus infections not only in animals but also in humans. As a complementary approach, the search for new antiviral drugs of natural origin has gained momentum. Currently, COVID-19 has emerged as the most intense and petrifying viral infectious disease all over the world to be handled by the human race. 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