Therapeutic potential of phytoconstituents of edible fruits in combating emerging viral infections

On Liberty is a philosophical essay by the English philosopher John Stuart Mill. Published in 1859, it applies Mill's ethical system of utilitarianism to society and state. Mill suggests standards for the relationship between authority and liberty.

Tariq Tell's review of my book "Capitalism, Jacobinism and International Relations: Revisiting Turkish Modernity", which is included in a symposium set to be published in Critical Sociology.

This article explores women's role in the alcohol trade in Cape Town between 1680 and 1795, particularly their use of social and symbolic capital against the background of their male counterparts' activities. While these women are conspicuous due to their direct involvement in the alcohol trade, they, too, did so within a context of spousal cooperation and family involvement. Several men entered the trade because of marriage into an alcohol retail family, while in many cases, wives were heavily involved in their husbands' entrepreneurial activities. Some families were involved in this trade over several generations, mostly through the female line. This paper demonstrates that the greater social and economic freedom accorded women in the Dutch Republic during this period also occurred in the colonial space, including Cape Town.

Received: 12 April 2021 | Revised: 20 June 2021 | Accepted: 21 June 2021 DOI: 10.1111/jfbc.13851 REVIEW Therapeutic potential of phytoconstituents of edible fruits in combating emerging viral infections Veerasamy Pushparaj Santhi1 | Poomaruthai Masilamani1,2 | Venkatraman Sriramavaratharajan3 | Ramar Murugan4 | Shailendra S. Gurav5 | Veerasamy Pushparaj Sarasu6 | Subbaiyan Parthiban1 | Muniappan Ayyanar7 1 Department of Fruit Science, Horticultural College and Research Institute for Women, Tamil Nadu Agricultural University, Tiruchirappalli, India 2 Anbil Dharmalingam Agricultural College and Research Institute, Tamil Nadu Agricultural University, Tiruchirappalli, India 3 Abstract Plant-derived bioactive molecules display potential antiviral activity against various viral targets including mode of viral entry and its replication in host cells. Considering the challenges and search for antiviral agents, this review provides substantiated data on chemical constituents of edible fruits with promising antiviral activity. The Virchow Biotech Private Limited, Hyderabad, India bioactive constituents like naringenin, mangiferin, α-mangostin, geraniin, punica- 4 lagin, and lectins of edible fruits exhibit antiviral effect by inhibiting viral replication Centre for Research and Postgraduate Studies in Botany, Ayya Nadar Janaki Ammal College (Autonomous), Sivakasi, India 5 Department of Pharmacognosy and Phytochemistry, Goa College of Pharmacy, Goa University, Panaji, India 6 Department of Clinical Microbiology, Government Medical College, Pudukkottai, India 7 Department of Botany, A.V.V.M. Sri Pushpam College (Autonomous), Bharathidasan University, Thanjavur, India Correspondence Muniappan Ayyanar, Department of Botany, A.V.V.M. Sri Pushpam College (Autonomous), Bharathidasan University, Poondi – 613503 Thanjavur, India. Email: asmayyanar@yahoo.com Funding information The writing of this manuscript was supported by the grant received from the Science and Engineering Research Board (SERB), Department of Science & Technology (DST), Government of India, New Delhi, India (Grant No. EMR/2016/007164) against IFV, DENV, polio, CHIKV, Zika, HIV, HSV, HBV, HCV, and SARS-CoV. The significance of edible fruit phytochemicals to block the virulence of various deadly viruses through their inhibitory action against the entry and replication of viral genetic makeup and proteins are discussed. In view of the antiviral property of active constituents of edible fruits which can strengthen the immune system and reduce oxidative stress, they are suggested to be diet supplements to combat various viral diseases including COVID-19. Practical applications Considering the increasing threat of COVID-19, it is suggested to examine the therapeutic efficacy of existing antiviral molecules of edible fruits which may provide prophylactic and adjuvant therapy with their potential antioxidant, anti-inflammatory, and immune-modulatory effects. Several active molecules like geraniin, naringenin, (2R,4R)-1,2,4-trihydroxyheptadec-16-one, betacyanins, mangiferin, punicalagin, isomangiferin, procyanidin B2, quercetin, marmelide, jacalin lectin, banana lectin, and α-mangostin isolated from various edible fruits have showed promising antiviral properties against different pathogenic viruses. Especially flavonoid compounds extracted from edible fruits possess potential antiviral activity against a wide array of viruses like HIV-1, HSV-1 and 2, HCV, INF, dengue, yellow fever, NSV, and Zika virus infection. Hence taking such fruits or edible fruits and their constituents/compounds as dietary supplements could deliver adequate plasma levels in the body to optimize Abbreviations: apoB, apolipoprotein B; CHIKV, chikungunya virus; CV-B3, coxsackievirus B3; DENV, dengue virus; DNA, deoxyribonucleic acid; EFCs, edible fruits and their constituents/compounds; EV71, human enterovirus 71; HBV, hepatitis B virus; hCMV, human cytomegalovirus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV-1, herpes simplex virus-1; HSV-2, herpes simplex virus-2; IFN-α, interferon alpha; IFN- γ, interferon gamma; IFV-A, influenza A virus; IFV-B, influenza B virus; MDCK, Madin-Darby canine kidney; MERS- CoV, Middle East respiratory syndrome virus; NSV, sindbis neurovirulent strain; PBMC, peripheral blood mononuclear cell; PEDV, porcine epidemic diarrhea virus; RNA, ribonucleic acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSV, respiratory syncytial virus; SARS, severe acute respiratory syndrome; Th1, T helper type 1; Th2, T helper type 2; TNF-α, tumor necrosis factor alpha; VLDL, very low density lipoprotein; VZV, Varicella-zoster virus; WHO, World Health Organization. J Food Biochem. 2021;00:e13851. https://doi.org/10.1111/jfbc.13851 wileyonlinelibrary.com/journal/jfbc © 2021 Wiley Periodicals LLC. | 1 of 16 2 of 16 | SANTHI eT Al. the cell and tissue levels and could lead to possible benefits for the preventive measures for this pandemic COVID-19 situation. KEYWORDS COVID-19, immune-modulators, phytochemicals, therapeutics, viral replication 1 | I NTRO D U C TI O N in 2012, thrombocytopenia syndrome causing SFTS bunyavirus in 2010, Ebola in West Africa during 2014–2016 and Zika virus in 2015 Viruses are one of the major causes of morbidity and mortality (Baseler et al., 2017; Bogoch et al., 2016; Vijaykrishna et al., 2010; Yu around the world that affect about five million people annually et al., 2011; Zumla et al., 2015). Of these, SARS-CoV and MERS-CoV (Andersen et al., 2020). There is an ever increase in the number of are caused by the coronaviruses, the major pathogens which target cases of human immunedeficiency virus, influenza, hepatitis C virus, the primary respiratory system in humans and pose severe threat and herpes simplex viruses which are leading causes of morbidity during the last two decades. and death in human (Khwaza et al., 2018). The respiratory tract in- Most recent viral emergence is SARS-CoV-2, coronavirus disease fections caused by different viral pathogens especially influenza 2019 (COVID-2019, a large group of ssRNA viruses) originated in viruses are considered a critical public health issue and causing mil- the middle of December 2019 from the city of Wuhan in China and lions of deaths worldwide annually, particularly with lower respira- now spreading to almost 220 countries with 178,503,429 confirmed tory tract infections (Farrag et al., 2019). To overcome this, novel cases including 3,872,457 deaths as of 05:44 pm CEST, 22 June 2021 molecules of natural products which hold effective therapeutic as reported to World Health Organization (http://who.sprinklr.com). potential against such viral diseases are the prime focus to prevent The SARS-CoV-2 is transmitted from human to human by respiratory the widespread infections and identification of antiviral mechanisms droplets, close contact with diseased persons, and possibly by oral from these drugs is attracted the researchers throughout the World and aerosol contact of diseased patients and airborne transmission (Patel et al., 2021). is extremely virulent and represents a foremost route to spread of Many viral diseases have so far been emerged from different parts disease (dos Santos, 2020). The major routes of transmission of virus of the world. Most of these viral diseases are infectious and pose are reported by new infections within the family members, health continuous challenge that can emerge or re-emerge at unpredict- care workers, and small to larger communities. Because of rapid able times in diverse climatic conditions. An emerging viral disease spread and nature of transmission, the WHO declared the COVID-19 is broadly referred as one of the newly evolved infectious disease as a pandemic disease with public health emergency of international or recently recognized or have not been witnessed earlier within a concern (Chikhale et al., 2020; Walls et al., 2020). specific population or geographical region (Gedif Meseret, 2020). The common symptoms of COVID-19 in humans include fever, Smallpox emerged from Asia and spread to Europe in 5th century, cough, dyspnea (shortness of breath), and in severe cases, the in- yellow fever emerged from America during the 16th century, dengue fection causes SARS, kidney failure, and pneumonia which leads to fever from South-east Asia, Africa, and North America during the death (Xian et al., 2020). Like SARS-CoV, the SARS-Cov-2 affects the 18th century, Spanish flu during 1918–1919 in almost all countries elderly people with underlying comorbidities and cause complica- which killed about 40 million people and HIV originated from Africa tions with bilateral interstitial pneumonia, acute respiratory distress in the second half of the 20th century which kills nearly 300,000 syndrome, acute cardiac injury, and secondary super-infections (Liu people every year (Chastel, 2007). et al., 2020). The potential cellular and molecular level pathogen- Since 1980s, the world has frequently been facing newly devel- esis of SARS-CoV-2 and its mechanisms responsible for different oped/formed pandemic viral infections which continue as a major malfunctions in the body are still unidentified (Filardo et al., 2020). threat to the human population. In the late 1990s, a highly patho- The recent pieces of evidence prove that the spike glycoproteins genic and deadly avian influenza A virus (H5N1) with several sub- of SARS-CoV-2 have structural similarity to the SARS-CoV (Lin types like H7N9, H9N2, and H7N3 spread from poultry to human et al., 2020; Walls et al., 2020). which becomes a pandemic disease (Luo (George) & Gao, 2020). The foremost step and important phenomenon in the coronavi- Nipah virus (paramyxovirus) has been identified as a major cause of rus infection is a viral entry into the host cell (interaction of host cell severe encephalitis in South-east Asian countries (Chua, 2000). through viral spike protein) followed by replication and spread into Severe acute respiratory syndrome (SARS), a respiratory dis- healthy cells. The natural therapeutic agents which block the entry ease caused by a novel coronavirus (SARS-CoV) was first identi- of viral DNA/RNA can be considered as potential antiviral therapeu- fied from China in early 2000 that affected people in 37 countries tics (Sayed et al., 2020; Zahedipour et al., 2020). There are many re- with over 8,000 infections and 774 deaths (Fouchier et al., 2003). semblances between the genetic makeup of MERS-CoV, SARS-CoV, Other viral diseases emerged in the beginning of 21st century are and SARS-CoV-2 (all three belong to a β-coronavirus family with the pandemic influenza in 2009 (caused by swine H1N1 influenza ssRNA, closer genome sequence homology, and almost same patho- A virus), the Middle East respiratory syndrome virus (MERS-CoV) genesis mechanism) and existing plant-based antiviral therapies used | SANTHI eT Al. 3 of 16 for SARS-CoV can also be examined against the COVID-19 (Bhuiyan promising results against the deadly viruses like coronaviruses in hu- et al., 2020). mans (Mani et al., 2020; Sinha et al., 2020). With the speedy spread of COVID-19, it is considered a major Research on antiviral agents from plant extracts has gained mo- alarming threat for almost all the countries and there is an increased mentum since 1950s when some of the traditional medicinal plants demand to carry out extensive research in developing effective vac- have proven effective against some pathogenic viruses. Antiviral cines or antiviral agents against the various strains of coronaviruses synthetic medicines administered for exterminating these infectious (Bhuiyan et al., 2020). The currently available drugs which are effec- viruses also impose side effects on human health thus demanding in- tive against some of the coronavirus strains can also be used against tervention of antiviral agents of plant origin. Post-exposure of human COVID-19, but this is not the perfect solution to overcome this pan- system to different viral infections requires effective therapeutic demic situation (Wilder-Smith et al., 2020). approaches to overcome severe infections and it is vital to develop novel antiviral agents from natural products (Chukwu Odimegwu & Gospel Ukachukwu, 2020). Plant-derived bioactives display antiviral 1.1 | Natural products as antiviral agents activity against the SARS viral targets including mode of viral entry and viral replication into host cells (Sayed et al., 2020). Natural products have made great contributions to human health. Given the facts of the ability of edible fruit constituents in im- Since ancient times, natural products from plant resources are used proving body immunity, we have tried to consolidate previously pub- in treating various diseases including viral infections. Subsequently, lished data on such research with antiviral potential. The objective many active constituents have been identified, isolated and their of this review was to gather information on antiviral properties of mechanisms of action in host organism have been elucidated by vari- bioactive constituents isolated from edible fruits, and efforts to ob- ous researchers (Liu & Du, 2012). Plants have the potential to pro- tain their efficient delivery. Since secondary metabolites of edible duce diverse secondary metabolites and maintain human health by fruits are reported to possess antiviral properties, these can also be inhibiting virus attachment, penetration, replication, and interfering utilized in combating COVID-19 in the current pandemic situation. intracellular signal activation pathways. So, it is essential to develop potential antiviral agents from natural products that have been traditionally used as antiviral agents which can be expected to prolong 1.2 | Review methodology the efficacy of drug therapy. Although the antiviral activity of several natural products against Several online bibliographical databases including PubMed, Scopus, various infectious viruses has been investigated, there is a lacuna and Web of Science were used to search literature on the antivi- in the development of natural drugs as antiviral therapies against ral effect of edible fruit constituents. An extensive literature search the coronaviruses which cause many diseases like bronchitis, gas- was conducted in the above databases with the terms “edible troenteritis, hepatitis, pneumonia and leads to death in birds, bats, fruits and phytoconstituents”, edible fruit constituents, “antiviral cats, and humans (Denaro et al., 2020; Islam et al., 2020). There are activity” along with “viral infections”, “viral replication”, “immuno- several classes of phytochemicals present in various parts of plants modulators”, and “immune boosters”. Only the reports that were which are reported to have many active principles with antiviral ac- in English were considered and included while compiling the data. tivity (Ghildiyal et al., 2020). The phytochemicals like phenolic com- The related articles linked to the retrieval list of articles were auto- pounds, alkaloids, flavonoids, saponins, quinines, tannins, terpenes, prompted during the literature search and reviewed for relevance. proanthocyanidins, proanthocyanins, lignins, glycosides, steroids, The references cited in the retrieved articles were also searched to organic acids, coumarins thiosulfonates with a broad spectrum of get further results. Chemical structures of compounds were drawn pharmacokinetics, are reported to have antiviral activity (Chukwu using ACD/ChemSketch software (ACD/Labs Release 2012, File ver- Odimegwu & Gospel Ukachukwu, 2020; Liu & Du, 2012). sion 14.01, Build 65,894). The bioactive plant compounds like rutin, quercetin, myricetin and baicalin, mangiferin, naringenin are effective against avian IFV, HSV-1, HSV-2, IFV, rhinovirus, DENV, poliovirus, adenovirus, Epstein-Barr virus, Mayaro virus, Japanese encephalitis virus, respi- 1.3 | Phytoconstituents (from edible fruits) as source of antiviral agents ratory syncytial virus, HCV, enterovirus, Newcastle disease virus, HIV, HBV, and Zika virus (Ben-Shabat et al., 2020). The mechanism Bioactive constituents like flavonoids and polyphenols extracted of action of these antiviral compounds is also well addressed. In the from various fruits shown to alleviate an inflammatory response last few decades, the success of plant-based effective therapies in adipocytes, macrophages, and other immune cells and improve led to much attention in the identification of antiviral lead mole- several metabolic disorders by modulating their mechanism (Li cules of plant origin (Lee et al., 2013). With the continuous search et al., 2020). Among the reported phytochemicals from edible on antiviral agents, plant-based natural compounds such as caffeic fruits, phenolic compounds were extensively studied to reduce acid, griffithsin, isobavachalcone, myricetin, psoralidin, quercetin, the risk of life-threatening diseases like cancer, heart problem, and saikosaponin B2, scutellarein, silvestrol, and tryptanthrin showed diabetes along with antimicrobial, antiviral, anti-inflammatory, and 4 of 16 | SANTHI eT Al. antiallergenic properties (Shahidi & Ambigaipalan, 2015). Several oxidative damage and improving the immune system) and it can plants of nutraceutical significance and their phytochemicals are also be effective antiviral agents against COVID-19. The existing reported to be effective against diverse viral respiratory infections evidences suggest that a number of phytoconstituents derived and altered the immune stimulation and inflammation modulating from fruits, spices, herbals, and roots possess a significant antioxi- effects (Patel et al., 2021). Due to the revival of interest in herbal dant, anti-inflammatory and virucidal functions and can reduce the medicines and novel compounds of nutraceutical plants, the AYUSH risk or severity of a wide range of viral infections by boosting the (https://www.ayush.gov.in/) systems of medicine promote lifestyle immune response mostly in people with deficient dietary sources modification and dietary management in day-to-day life in the pre- (Mrityunjaya et al., 2020). vention of COVID-19 by improving immunity in the body. Many functional foods and substances naturally possess diverse Antioxidants present in edible fruits can scavenge reactive ox- bioactive compounds that have been scientifically proven to have ygen species and inhibit the NF-kB-mediated inflammation which immune-boosting properties and antioxidant present in such foods leads to inhibit oxidative stress (Wood & Gibson, 2009). The excess or edible fruits can be directly obtained as dietary supplements amount of free radicles produced in the body by various factors (López-Varela et al., 2002). For example, hesperidin from orange could cause oxidative stress which leads to chronic diseases, so the (one of the renowned source for its vitamin and flavonoids content) increased consumption of edible fruits with a rich amount of antiox- attracted the attention of researchers, since the compound has a low idants in the daily diet will prevent or slow down the oxidative stress binding energy, both with the SARS-CoV-2 spike protein and with (Sun et al., 2002). Several flavonoid compounds extracted from edi- main protease which transforms the early proteins of virus into a ble fruits possess antiviral activity against a wide array of viruses like complex responsible for viral replication in host cells as evidenced HIV-1, HSV-1 and 2, HCV, INF, dengue, yellow fever, NSV, and Zika by computational methods (Bellavite & Donzelli, 2020). Flavonoid virus infection (Cataneo et al., 2019). compounds have the capacity to bind with functional domains of the Various bioactive components present in the edible fruits could SARS-CoV-2 protein which referred as the viral surface glycoprotein have complementary and overlapping mechanisms of action by per- that required for early attachment and internalization of viruses into forming as antioxidants, stimulant factor in the immune system, mo- the host cells (Patel et al., 2021). lecular level regulators of gene expression in cell proliferation and apoptosis, hormone metabolism as well as antimicrobial and antiviral agents (Liu, 2013). The phytochemicals present in the edible fruits 1.4 | Naringenin, a potent antiviral compound act as immune-modulators by enhancing the cell-mediated immunity and activate non-specific immune responses and activation of The flavonoid group of compounds are effective against several necessary immune cells in the body result in the production of vital viruses mainly HCV by blocking its entry into host cell and can al- components like interferons, cytokines, and chemokines which are leviate HCV infection by reducing apolipoprotein B100 (apoB100) served as stimulators in the immune responses (Yang & Wang, 2020). secretion which is required for infection of HCV (Hernández-Aquino The phytochemicals tested for antiviral activity are abundant in var- & Muriel, 2018). Naringenin (4′,5,7-trihydroxy flavanone; Figure 1a) ious nuts, fruits, berries, and its active components possibly have is one of the most important naturally occurring flavonoids widely the capacity to diminish infection and replication of many viruses distributed in various fruits and vegetables and one of a promis- (Brijesh et al., 2009). ing drug candidate in the development of anti-COVID-19 therapy The review also provided an overview of likely effects of the (Tutunchi et al., 2020). intake of edible fruits constituents to strengthen the immune cells The addition of naringenin at 250, 125, and 62.5 μM to Huh-7.5 by reducing the oxidative stress in host body system which in turn cells infected with DENV 1,2,3, and 4 serotypes proved the ability inhibit the viral attachment and replication on the host cell. Several to impair and reduce the DENV replication and its maturation with active molecules from the fruits like geraniin from rambutan, nar- effectiveness similar to IFN-α 2A (a well-known antiviral cytokine) ingenin from citrus and grapes, (2R,4R)-1,2,4-trihydroxyheptadec- and ribavirin treatments (Frabasile et al., 2017). After 24 hr of nar- 16-one from avocado, betacyanin from red dragon, mangiferin and ingenin treatment at 62.5 μM concentration (identified as non-toxic isomangiferin from mango, procyanidin B2 and quercetin from apple, concentration), it effectively reduced the percentage of Huh-7.5 punicalagin from pomegranate, marmelide from bael, jacalin lectin DENV-1 infected cells and reduced the number of infected CD14+ from jackfruit, and a banana lectin from banana have been isolated cells in human PBMCs and number of infectious virus particles in the and showed promising antiviral properties against different patho- culture. It was also revealed that, after 6 hr of naringenin treatment, genic viruses (Table 1). Several of these phytochemicals of edible the DENV-1 infection reduced the DENV-titer which confirms the fruits have complementary and overlapping mechanisms of action potential anti-DENV activity of this flavanone compound. including potential antiviral effect by either inhibiting the formation Naringenin impairs the ZIKV replication and efficiently reduced of viral DNA/RNA or inhibiting the activity of viral reproduction in- the number of ZIKV infected human monocyte-derived dendritic side the host cell. cells at 125 μM (Cataneo et al., 2019). From the molecular mod- The EFCs possessed a vast range of antiviral activity through dif- elling data, naringenin’s ability to interact with viral protease (al- ferent mode of action (e.g., inhibition of viral replication, reducing losteric inhibitors) is analyzed and the molecular target of naringenin | SANTHI eT Al. TA B L E 1 5 of 16 List of phytochemicals isolated from edible fruits with antiviral properties Phytochemical Viruses studied Observation References Naringenin HBV Infectivity of viruses in the host cell by targeting viral envelope by reverse transcriptases Alam et al. (2017) HCV Reduction in lipid profile and liver enzyme aspartate transaminase with a decreased infectivity and spread of infection Goncalves et al. (2017) DENV-1,2,3 & 4 Reduction in Huh-7.5 DENV-1 infected cells and CD14+ cells in human PBMCs Frabasile et al. (2017) DENV-2 50% of reduction in viral RNA infection Zandi et al. (2011) ZIKV Reduction in the number of infected hmd-DCs by impairing the viral replication Cataneo et al. (2019) HCV Minimum binding energy with NS2 protease and target protein for antiviral activity were analysed by in silico method Sajitha Lulu et al. (2016) CHIKV Production of viral proteins was prevented in a host cell by which leads to killing 50% of infected cells Ahmadi et al. (2016) NSV 80% of viral replication was inhibited by blocking the infectivity Paredes et al. (2003) HCV 70% of inhibition in the secretion of HCV core and HCV RNA which leads to inhibition of apoB100-dependent HCV secretion Nahmias et al. (2008) HCV Assembly of infectious HCV particles blocked by activating the peroxisome proliferator-activated receptor-α and reduction in VLDL production Goldwasser et al. (2011) HSV-1 56.8% of plaque reduction was observed with decreased viral replication Zheng and Lu (1990) HIV The significant cytopathic effect in infected cells Guha et al. (1996) Poliovirus Increased virulence and replication of the virus in host cells was observed in different stages of poliovirus Rechenchoski et al. (2018) HSV-2 Viral replication was significantly reduced with decreased plaque formation in HeLa cells Zhu et al. (1993) HIV-1IIIB & HIV-1RF The inhibitory activity is effective against peptidic protease inhibitor-resistant strains in lower concentrations Wang et al. (2011) Isomangiferin HSV-1 69.5% of plaque reduction with decreased viral replication Zheng et al. (1990) α-Mangostin HIV-1 Significant inhibitory activity with decreased viral replication Chen et al. (1996) DENV-2 Viral replication was reduced by more than 50% and increased gradually by post-infection Sugiyanto et al. (2019) DENV-1,2,3 & 4 The infection rate was reduced by 47%–55% by inhibiting the cytokine and chemokine transcription Tarasuk et al. (2017) DENV-2 100% inhibition of viral replication was noticed by preventing the viral attachment at early stages of infection Abdul Ahmad et al. (2017) EV71 Addition of geraniin at 2 hr post EV71 infection on human rhabdomyosarcoma cells inhibited infectious virus yield and viral RNA replication Yang, Zhang, et al. (2012) Geraniin significantly enhanced the survival rate of EV71 infected mice and decreased viral replication in muscle tissues Yang, Zhang, et al. (2012) The compound inhibited the replication of HSV-2 with an IC 50 and IC90 of 18.4 ± 2.0 and 37.6 ± 2.3 µM, respectively, and inhibited the replication of HSV-1 with an IC50 of 35.0 ± 4.2 µM. Yang et al. (2007) Mangiferin Geraniin DENV-1,2 (Continues) 6 of 16 | TA B L E 1 SANTHI eT Al. (Continued) Viruses studied Observation References HIV-1 Significant inhibitory effect against the replication of HIV-1 showed with IC50 and EC50 of 1.8 ± 0.5 µg/ml and 0.24 ± 0.10 µg/ml respectively in MAGI cells Notka et al. (2003) The significant anti-HIV activity was recorded in CD4+ lymphoid cells MT4 at even low concentrations Notka et al. (2003) EV71 Viral replication was inhibited with reduced cytopathic effect on rhabdomyosarcoma cells Yang, Zhang, et al. (2012) HSV-1 Viral infectivity and replication were reduced 8-fold with no toxicity Houston et al. (2017) HSV-2 100% inhibition of viral infection was recorded in Hep-2 cells of human epithelial tissue Arunkumar and Rajarajan (2018) HBV Punicalagin down regulated the level of cccDNA formation in HBV without inhibiting viral RNA transcription and DNA replication in the host cells. Liu et al. (2016) IFV-A The compound significantly inhibiting the agglutination of chicken RBCs in the IFV-A and prevents the proliferation of IFV-A in both single and multiple cycle growth conditions in infected MDCK cells Haidari et al. (2009) (2R, 4R)-1,2,4trihydroxyheptadec-16-one DENV-1,2,3 & 4 The survival rate of DENV infected mice was increased by stimulating the NF-κB- mediated IFN responses with no cytotoxicity Wu et al. (2019) BanLec (Banana lectin) HIV-1 Attachment of virus into the host cell was prevented in very low concentrations Mazalovska and Kouokam (2018) HIV Mitogenicity and significant antiviral properties were observed Swanson et al. (2015) Influenza A, B Engineered BanLec exhibited antiviral activity at 10 μg/ml Covés-Datson et al. (2020) HIV Penetration of viral particles and viral envelopes into the host cells was observed with less toxicity Akkouh et al. (2015) HIV Inhibition of viral entry into the host cell and spread of infection was reduced by binding to the glycosylated viral envelope Swanson et al. (2010) HIV-1 Inhibition of viral replication by binding to membrane molecules together with CD4 Favero et al. (1993) HSV-2, VZV, hCMV 50% of inhibition and viral replication was noticed with mitogenic action for NK lymphocyte Wetprasit et al. (2000) Lectin like compounds (Japanese plum) H1N1, H3N2 Prevents the attachment of viral haemagglutination in host MDCK cells before viral adsorption Yingsakmongkon et al. (2008) Betacyanin (Fractions) DEN-V 95% of viral replication and infection was inhibited with no cytotoxicity Chang et al. (2020) Marmelide Coxsackievirus B3 Loss of infectivity was observed with inactivating the viruses at 125 µg/ml for 1 hr at 37℃ Badam et al. (2002) Phytochemical Punicalagin Jacalin (Jackfruit lectin) is NS2B-NS3 protease. It is proved that naringenin displays strong down-regulating the production of viral proteins that are involved in antiviral activity by affecting viral replication or assembly of viral viral replication (Ahmadi et al., 2016). Administration of naringenin particles especially post-infection (Cataneo et al., 2019). Antiviral at 25 μg/ml in baby hamster cells 21 clone 15 (BHK-21) infected with activity of naringenin is analyzed by protein prediction study using sindbis neurovirulent strain (NSV) inhibited the viral replication up molecular modelling protocol, in which it showed minimum binding to 80% by blocking the infectivity of the NSV (Paredes et al., 2003). energy of 7.97 kcal/mol with NS2 protease and all the observed li- The HCV is the foremost cause for chronic liver diseases asso- gands present within the binding pocket of target protein (Sajitha ciated with circulating lipoproteins, cholesterol, and lipid pathways Lulu et al., 2016). and it progresses to a chronic state in about 70% of patients, ul- Naringenin extracted from the citrus fruits possesses significant timately causing cirrhosis and hepatocellular carcinoma (Nahmias antiviral activity by inhibiting the CHIKV replication in a host cell and et al., 2008). Their study also suggested to take naringenin as | SANTHI eT Al. (b) (a) (e) (c) (f) 7 of 16 (d) (g) (h) F I G U R E 1 Major phytochemicals isolated from edible fruits with potential antiviral properties. (a) Naringenin; (b) Mangiferin; (c) Isomangiferin; (d) α-Mangostin; (e) Geraniin; (f) Punicalagin; (g) Betacyanins; (h) Marmelide supplementation with the diet to HCV patients since, the compound presence of 0.14 μg/mg concentration of naringenin in ethanolic leaf has the ability of reduction in HCV viral load by inhibiting viral secre- extracts of the plant Guiera senegalensis J.F. Gmel. (Combretaceae) tion and possibly by allowing uninfected cells to regenerate which showed significant anti-HBV activity by RP-HPTLC method which potentially increasing the overall rate of viral clearance in the pa- supports the possible role of the compound in inhibition of HBV tients. The HCV replication depends on the expression of apoB100 gene expressions and DNA replication (Alam et al., 2017). and assembly very-low-density lipoprotein (VLDL) in host cells especially in human hepatocytes (Huang et al., 2007). The Huh-7.5.1 cells infected with HCV administered with 200 μM naringenin for 24 hr inhibits the secretion of HCV core and HCV 1.5 | Mangiferin against HSV-1, 2, HIV, and poliovirus positive-strand RNA followed by inhibition of apoB100-dependent HCV secretion in a dose-dependent manner (Nahmias et al., 2008). Mangiferin (1,3,6,7-tetrahydroxy-C2-β-D-glucoside) is a xanthone Naringenin obtained from grapefruit [Vitis vinifera L., Vitaceae] re- glucoside found in significant level in higher plants and a major com- pressed VLDL secretion, microsomal triglyceride transfer protein pound in various parts of Mango [Mangifera indica L., Anacardiaceae] activity, and transcription of 3-hydroxy-3-methyl-glutarl-coenzyme such as fruit peel, kernel, stalk, leaf, bark, and seed. It possesses A reductase and acyl-coenzyme A cholesterol acyl-transferase lead- immune-modulating effects on different oxidative mechanisms in ing to a reduction in 80% of HCV by silencing the apoB mRNA in curing various disorders (Wang et al., 2011). Mangiferin (Figure 1b) infected cells and caused a 70% reduction in the release of apoB100 and isomangiferin (Figure 1c) isolated from the fruit pulp of mango as well as HCV replication (Nahmias et al., 2008). have significant antiviral property against HSV-1 with 56.8% and Naringenin obtained from the grapefruit significantly inhibited 69.5% of average plaque reduction rates respectively and have com- the secretion of apoB and HCV RNA followed by a decreased level parable results over the standard drugs like acyclovir, idoxuridine, of HCV core protein secretion (Goldwasser et al., 2011). Naringenin and cyclocytidine (Zheng & Lu, 1990). Mangiferin isolated from the inhibits the HCV secretion by blocking the assembly of infectious leaves of mango showed an EC50 and EC99 at the concentration of HCV particles and the antiviral activity is mediated by activating per- 33 and 80 mg/ml against HSV-2 plaque formation in HeLa cells and oxisome proliferator-activated receptor-α led to a reduction in VLDL reduces viral replication efficiently in the late event of HSV-2 repli- production which is necessary for the secretion of HCV particles in cation (Zhu et al., 1993). host cells. Naringenin exhibited significant virucidal activity against the Mangiferin purified from the fruits of Mango at a concentration of 10 µg/ml significantly reduced the cytopathic effect of HIV in DENV-2 type with the IC50 of 52.64 μg/ml by inhibiting the DENV-2 susceptible human leukemia cells and showed a EC50 of the drug at RNA level at 50 μg/ml concentration (Keivan et al., 2014). The 3.59 µg/ml and compound did not found any substantial change in 8 of 16 | the uninfected human leukemia cells when added with the differ- SANTHI eT Al. and DENV-3 was recorded by decreasing the cytokine (IL-6 and ent doses of mangiferin (Guha et al., 1996). Mangiferin purified from TNF-α) and chemokine (RANTES, MIP-1β, and IP-10) transcription. the root and rhizome extracts of anemarrhena (Anemarrhena aspho- Therefore, α-mangostin can be considered as a potent antiviral agent deloides Bunge, Asparagaceae) exhibited dose-dependent anti-HIV than the synthetic ribavirin due to its superior activity. In the coun- inhibitory activity on HIV-1 induced syncytium formation in HIV-1IIIB tries where all the four DENV serotypes are common which leads to and HIV-1RF with the EC50 of 7.13 μg/ml (16.90 μM) and 15.45 μg/ml severe secondary infections, α-mangostin is ideal and an effective (36.61 μM) respectively (Wang et al., 2011). In the time-of-addition antiviral drug (Sugiyanto et al., 2019). assay, when mangiferin was added at various times after HIV-1IIIB In vitro prophylactic effect of α-mangostin (extracted from the infected C8166 cells, the compound blocked HIV-1 p24 antigen pro- pericarps of mangosteen) was significantly inhibited the replication duction after 12 hr. It is also observed that mangiferin is effective of CHIKV in Vero E6 cells with the 100% reduction of virus titer at against HIV-1 peptidic protease inhibitor-resistant strains and less 8 μM concentration under cotreatment condition (Patil et al., 2021). effective against the protease inhibitor-resistant strains of HIV-1. Also, reduction of CHIKV replication in serum and muscles of in- Mangiferin isolated from the fruit peels of mango showed good fected mice models showed nearly 99% of reduction in CHIKV RNA inhibitory property against poliovirus-1 with 97.8%, 84.2%, and copies with low and high dose of α-mangostin. The molecular dock- 57.1% of viral inhibition at 200, 100, and 50 μg/ml concentrations, ing study revealed that α-mangostin interacts with the E2-E1 het- respectively (Rechenchoski et al., 2018). The overall IC50 was re- erodimeric glycoprotein and the outcomes suggest that α-mangostin corded as 53.5 μg/ml and after 12 hr of mangiferin treatment 62.7% can possibly inhibit the replication of CHIKV infection through mul- of viral inhibition was recorded at the concentration of 100 μg/ml. tiple target proteins (Patil et al., 2021). However, during the late stages of viral replication, even at a low concentration (25 μg/ml) mangiferin exhibited strong virucidal activity with 100% of viral inhibition of viral adsorption. 1.6 | α-Mangostin against DENV, HIV, and CHIKV 1.7 | Geraniin against DENV-2, EV71, HSV-1,2, and HIV Geraniin (Figure 1e) is an ellagitannin with a complex chemical structure belongs to a hydrolysable tannin group and commonly found The α-mangostin (Figure 1d) is the major xanthone extracted from in edible fruits like common berries (raspberries, strawberries, the pericarps and bark of the mangosteen (Garcinia mangostana L., and blackberries), pomegranate, almonds, rambutan, and walnuts Clusiaceae) and holds a wide range of biological activities such as an- (Palanisamy et al., 2011). Gareniin has a wide range of pharmaco- timicrobial, antiparasitic, antioxidant, anti-inflammatory, anti-tumor, logical activities and possesses antioxidant, antibacterial, antifungal, antiobesity, cardioprotective, and antidiabetic (Ibrahim et al., 2016). antitumour, antihypertensive, antinociceptive, radioprotective, and This xanthone compound showed noteworthy pharmacological ef- antiviral properties (Yang, Zhang, et al., 2012). fects in in vitro studies as well as in experimental animal models through various mechanisms of action. Geraniin isolated from the rambutan [Nephelium lappaceum L., Sapindaceae] fruit rind reduces the infectivity of DENV-2, represses The ethanolic extract of mangosteen fruit is considered as a the viral attachment, and prevents DENV-2 replication upto 100% potent inhibitor of HIV-1 protease activity and the antiviral prop- of inhibition during early stages of viral infection (Abdul Ahmad erty of this fruit is due to the presence of purified molecules like et al., 2017). Geraniin effectively reduced the DENV-2 infectivity at α-mangostin and γ-mangostin (Chen et al., 1996). The administra- 3.28 μM of concentration in a dose-dependent manner. It was also tion of α-mangostin (obtained from the pericarps of mangosteen) observed that the mechanism of geraniin is either through the bind- to dengue patients during the acute phase of illness may decrease ing or disruption to the DENV-E protein by inhibiting attachment infection severity by activating the host’s immune response through of the virus to cellular receptors and binding of geraniin to E-DIII mechanism of interfering DENV NS5 protein activity which is essen- prevents protein-protein interaction between host cells and DENV-2 tial for DENV replication and reducing transcriptional responses of thus preventing viral attachment and entry of DENV into the host cytokines (Sugiyanto et al., 2019). cells (Abdul Ahmad et al., 2017). Geraniin produced a low cytotoxic- The effect of α-mangostin against the DENV infection and post- ity on human rhabdomyosarcoma cells in plaque reduction assay and infection in PBMCs, TNF-α and IFN- γ cytokines revealed that in- addition of 20 μg/ml concentration of geraniin (with an IC50 of 10 μg/ creasing concentration of α-mangostin inhibits the viral replication ml) at 2 hr post EV71 infection positively inhibited the infectious by more than 50% with the IC50 of 5.47 and 5.77 μM for 24 and virus yield and viral RNA replication (Yang, Zhang, et al., 2012). In an 48 hr of post-treatments, respectively (Sugiyanto et al., 2019). The in vivo study, the treatment of 0.4 and 1.0 mg/kg doses of geraniin α-mangostin inhibits DENV production in cultured hepatocellular significantly enhanced the survival rate of EV71 infected mice with carcinoma HepG2 and Huh-7 cells, and cytokine/chemokine ex- 35% and 40%, respectively with a reduction in mortality and de- pression in HepG2 cells (Tarasuk et al., 2017). DENV virus-infected creased viral replication in muscle tissues (Yang, Zhang, et al., 2012). cells treated with α-mangostin considerably reduced the infection Geraniin extracted from the whole plant parts of Phyllanthus uri- rates 47%–55%, and complete inhibition in production of DENV-1 naria L. [Phyllanthaceae] showed promising anti-HSV-1 and HSV-2 | SANTHI eT Al. 9 of 16 activity (Yang et al., 2007). The compound efficiently inhibited the virucidal action with a resulting log reduction of 4.6 ± 0.16 mg/ replication of HSV-2 with the IC50 and IC90 of 18.4 ± 2.0 µM and ml from 2.4 ± 0.9 mg/ml. Punicalagin exhibits a strong anti-HSV-2 37.6 ± 2.3 µM concentrations, respectively, and showed strong activity with 100% inhibition at 31.25 μg/ml and 50% of inhibition inhibitory effect against the replication of HSV-1 with the IC50 of at 15.625 μg/ml in HEp-2 cells of human epithelial tissue-specific 35.0 ± 4.2 µM concentration of geraniin. The purified fraction of (Arunkumar & Rajarajan, 2018). Liu et al. (2016) made an attempt Phyllanthus emblica leaves enriched with geraniin showed significant to examine the anti-HBV activity of punicalagin through cell-based inhibitory effect against the replication of HIV-1 with the IC50 and cccDNA (covalanetly closed circular DNA which formed from circu- EC50 values of 1.8 ± 0.5 µg/ml (at a concentration of 1.9 ± 0.5 µM) lar partially double-strand DNA) accumulation and stability assay and 0.24 ± 0.10 µg/ml (at a concentration of 0.25 ± 0.1 µM), respec- in HepDES19 and HepG2.117 cell lines. Their study revealed that, tively, in MAGI cells (Notka et al., 2003). Likewise, geraniin showed punicalagin efficiently down regulated the level of cccDNA forma- decent anti-HIV-1 activity in the CD4+ lymphoid cells MT4 with the tion in HBV without inhibiting RNA transcription and DNA replica- EC50 and CC50 values of 0.46 ± 0.17 µg/ml (0.48 ± 0.18 µM concen- tion in host cells that indicates the role of punicalagin in cccDNA tration) and 13.53 ± 2.30 µg/ml (14.20 ± 2.41 µM concentration) metabolism. respectively. 1.8 | Punicalagin against IFV-A, EV71, HSV-1, 2, and HBV 1.9 | (2R,4R)-1,2,4-Trihydroxyheptadec-16-one against DENV The compound (2R,4R)-1,2,4-trihydroxyheptadec-16-one (THHY) Punicalagin (Figure 1f) is a large polyphenolic compound which be- extracted and purified from the unripe avocado [Persea americana longs to the hydrolysable tannins and identified as a major active Mill., Lauraceae] fruits possesses anti-DENV activity with the EC50 constituent of pomegranate [Punica granatum L. Lythraceae] fruits of 14.61 ± 2.4, 10.98 ± 1.9, 12.87 ± 1.7, and 14.61 ± 2.1 µM on especially in fruit rinds (Yang, Xiu, et al., 2012). The compound is DENV-1, 2, 3, and 4 serotypes, respectively, with no observable considered as potential free radical scavengers (antioxidant) which cytotoxicity to host cell by stimulating the NF-κB-mediated IFN re- have superoxide anion, singlet oxygen, and hydroxyl radical scav- sponses against the studied four serotypes (Wu et al., 2019). THHY enging abilities with lipid peroxidation inhibitory activity along also prevents DENV replication in a time-dependent manner and with several health benefits (Kulkarni et al., 2007). Punicalagin also treatment of virus-infected mice with THHY increased the survival possess a wide range of pharmacological effects including antimi- rate ensuring that this fruit as a potential dietary resource to develop crobial, antioxidant, chemo-preventive, hepatoprotective, immune- a supplement to treat DENV and related viral diseases. stimulant, antiproliferative, apoptotic, and antiviral activities (Yang, Xiu, et al., 2012). Punicalagin is the active anti-influenza component of the fruit rind extract of pomegranate which increases the inhibitory effect 1.10 | Lectins against Flu, HIV-1 & 2, HSV-2, VZV, and CMC synergistically with oseltamivir by inhibiting the agglutination of chicken RBCs in the IFV-A (Haidari et al., 2009). The compound also Lectins are principally proteins that bind to specific carbohydrate has the potential to inhibit the proliferation of IFV-A in both single structures and different lectins isolated from plants, animals, fungi, and multiple cycle growth conditions in the infected MDCK cells. and microbes are reported to be effective against HCV, influenza The in vitro and in vivo analysis on the antiviral effect of punicalagin A/B, HSV-1 & 2, Japanese encephalitis virus, and coronaviruses with (isolated from fruit rind extract of pomegranate) on EV71 showed more focus on the anti-HIV property (Mazalovska & Kouokam, 2018). that the compound decreases the cytopathic effect on rhabdomyo- In general, the lectins of plant origin encloses tandem repeats within sarcoma cells after treatment with 15 µg/ml of punicalagin at 2 hr the primary sequence and exist in the form of monomeric and higher post EV71 infection significantly inhibits the viral replication (Yang, multimeric states comprised of β-sheets (Mitchell et al., 2017). In Xiu, et al., 2012). The punicalagin also impressively prolonged the antiviral therapies, lectins can neutralize different viruses includ- survival time and reduced the mortality of mice models when admin- ing influenza and HIV making them potential targets in developing istered with dose of 0.4, 1, or 5 mg/kg body weight which recorded novel antiviral drugs. As natural proteins, lectins target the sugar 20, 40, and 38% of long-term survivor of infected mice. moieties of a SARS-CoV spike protein (glycoprotein) and primarily Punicalagin (extracted from fruit rind of pomegranate) at mannose binding lectins indicated their interference with virus at- very low concentration shows a strong virucidal log reduction of tachment to SARS-CoV spike protein making them early entry inhibi- 8.93 ± 0.35 (at 0.05 mg/ml concentration) on a mass to mass basis tors (Keyaerts et al., 2007). and reduces infectivity of the HSV-1 by inhibiting the viral replica- The lectin (BanLec) isolated from the banana fruits [Musa tion in T75 of Vero cells infected with HSV-1 (Houston et al., 2017). acuminata Colla, Musaceae] is one of the jacalin-related (lectin iso- It was also observed that, when the punicalagin was added with lated from Jackfruit) lectins which have the affinity towards high- ZnSO 4 at 0.14 mg/ml concentration it potentially increased the mannose structures. BanLec can inhibit various HIV-1 isolates in 10 of 16 | SANTHI eT Al. low nano-molar range with a concentration-dependent manner and also in red beetroot (as a red betacyanin and a yellow betax- thus preventing the attachment of virus into host cell (Mazalovska anthin), various green amaranth species. Betacyanins extracted & Kouokam, 2018). BanLec is one of the potent mitogens form mu- from various sources of fruits and other plant parts show a wide rine T-cells and when a mutation happens within sugar-binding site range of pharmacological effects including antioxidant, antibacte- of BanLec, it reduces mitogenic activity without affecting HIV neu- rial, antifungal, anticancer, and antilipidemic activities (Gengatharan tralization and mitogenicity, besides antiviral activities of BanLec re- et al., 2015). The betacyanin (Figure 1g) fractions obtained from red quires association with N-glycans (Swanson et al., 2015). dragon fruit (Hylocereus costaricensis [F.A.C. Weber] Britton & Rose, The H84T BanLec, an engineered banana lectin is effective Cactaceae) shows a significant virucidal effect against the DENV-2 against an array of influenza virus strains that possesses significant with 95% of inhibition at 379.5 µg/ml (with an IC50 of 126.70 μg/ antiviral activity better than most of the previously tested lectins ml) without any cytotoxicity supporting its efficiency as a potential (Covés-Datson et al., 2020). The engineered lectin-like H84T BanLec antiviral agent (Chang et al., 2020). Their study on the virucidal ef- is a broad-spectrum lectin capable of inhibiting both influenza A and fect of betacyanin fractions showed the ability of the compound to B type viruses, which could be used as a potent therapeutic agent inactivate the extracellular DENV-2 particles and decrease the viral against a diverse array of viral strains. The antiviral lectins can pre- infection in dose-dependent manner. vent penetration of viral pathogens into the host cells which are suitable for topical applications with lower toxicity than other commonly practiced antiviral therapies and the glycoprotein covered 1.12 | Marmelide against CV-B3 retroviruses like HIV and other viruses having similar type envelopes (Akkouh et al., 2015). BanLec binds to glycosylated viral envelope and The exposure of CV-B3 to marmelide (Figure 1h) isolated from the inhibits the cellular entry of the virus into a host cell and suppresses bael [Aegle marmelos Corr., Rutaceae] fruits causes a total loss of HIV-1 infection. This activity is identical to the existing snowdrop infectivity by inhibiting the formation of viral cells followed by the lectin-like Griffithsin, known anti-HIV drugs like maraviroc and T-20 inactivation of viruses. The addition of marmelide at a concentration (Swanson et al., 2010). Likewise, intranasal administration of H84T of 125 μg/ml for 1 hr on CV-B3 in Vero cells resulted in increased BanLec after 4 hr post infection of mice model with H1N1 efficiently inhibition of infectivity that signifies the effect of the compound blocked viral infection with about 75% of survival rate with even at (Badam et al., 2002). Therefore, marmelide could be a novel virucidal lower dose of 0.03 mg (Swanson et al., 2010). agent against the CV-B3 by further studying the mode of action by The jacalin, obtained from the fruits of jackfruit [Artocarpus het- molecular level studies, since the mode of action marmelide could erophyllus Lam. Moraceae] and a jacalin-α chain-derived peptide in- be associated with the earlier and later stages of virus replication in hibits HIV-1 infection in human T lymphoid cells exerts its anti-HIV the host cell. activity through binding to membrane molecules together with CD4 and as like other lectins the jacalin may not interact with external glycoprotein of the virus (Favero et al., 1993). Lectin derived from 2 | CO N C LU D I N G R E M A R K S jackfruit seeds inhibits HSV-2, VZV, and hCMV and shows mitogenic action for NK lymphocytes (CD16+/CD56+) (Wetprasit et al., 2000). Among the reported antiviral compounds of edible fruits, naringenin, Lectin like molecules isolated from the concentrated fruit juice of mangiferin, and lectins are much effective against more number of Japanese Plum [Prunus mume Siebold & Zucc., Rosaceae] exhibits an- viruses as reported by various researchers. Figure 2 displays the an- tiviral activity against the human influenza A viruses like A/PR/8/34 tiviral activity of phytochemicals isolated from the edible fruits with (H1N1), A/Aichi/2/68 (H3N2) and A/Memphis/1/71 (H3N2) in host a different mode of action. The components α-mangostin, betacya- Mardin-Darby canine kidney (MDCK) cells before viral adsorption nins, geraniin, naringenin, and (2R,4R)-1,2,4-trihydroxyheptadec-16- (Yingsakmongkon et al., 2008). The concentrated fruit juice extract one shown potential candidates against dengue virus serotypes. The of Japanese Plum prevents and reduces the infectivity of human in- figure also clearly shows the antiviral effect of these constituents fluenza A virus and it may be due to the presence of lectin-like com- by inhibiting the viral replication, plaque formation, viral replication, pounds (with high molecular weight) which inhibits the attachment attachment of the virus into a host cell, blocks the assembly of viral of viral hemagglutination on host cell surfaces. particles, down-regulating the production of viral proteins which in turn lead to a reduction in viral infectivity in host cells. The anticipated role of EFCs in the management of COVID-19 1.11 | Betacyanins against DENV-1 as evidenced by their efficacy against other viral diseases is shown in Figure 3. It was evident that, as soon as the SARS-CoV-2 virus Betacyanin is a red-violet pigment belongs to betalains (pigments crosses the respiratory tract, it spreads into the lung cells with its group) which are water-soluble, nitrogen containing pigments and specific spike protein which can couple with ACE-2 receptors of can exist as the red-violet betacyanins or yellow betaxanthins the host cell. The EFCs may directly damage the virus structure and (Gengatharan et al., 2015). These groups of compounds are com- inhibit the entry of viruses by disturbing the connections between monly available in several fruit crops like red dragon fruit, cacti fruit viral spike proteins and host ACE-2 receptors. Also, EFCs may inhibit | SANTHI eT Al. 11 of 16 F I G U R E 2 Compounds isolated from edible fruits and its multi-target antiviral activity with a described mechanism. The different colored double arrow represents specific phytochemicals with respective antiviral properties with various actions in a host cell. LTN (Lectins)–Pink; PCN (Punicalagin)–Light blue; MME (Marmelide)–Light Green; BCN (Betacyanins)–Green; GRN (Geraniin)–Dark Red; NGN (Naringenin)–Red; AMSN (α-mangostin)–Dark Blue; THH ([2R, 4R]-1,2,4-trihydroxyheptadec-16-one)–Orange; MFR (Mangiferin)–Purple the internalization of the virus into the host cell. The EFCs may coronavirus outbreaks like SARS-CoV and MERS CoV in the recent inhibit viral replication by suppressing the protease (Mpro), RNA- past and other major life threatening viral diseases like HCV and INF dependent RNA-polymerase (RdRp), and protein synthesis. were successfully treated by various herbal drugs and phytoconstit- The figure also evidences the effect of EFCs in reducing oxida- uents of nutraceuticals (Patel et al., 2021). It was also advised that tive damage caused during COVID-19 infection via surplus ROS/ the prevention of viral respiratory related infections requires intake RNS and free radicals. It was reported that, increased utilization of vitamin C in the form of commercial drugs or regular consumption of free radicals might have impacted negatively in the COVID-19 of fruits like orange, lemon, etc. which contains hesperidin as major patients who are prone to depleted levels of antioxidants like vita- compound (Bellavite & Donzelli, 2020). Hence taking such fruits mins, enzymes and some mineral elements (Muhammad et al., 2021). or EFCs as dietary supplements delivers adequate plasma levels in Likewise, lectins of different plant origin (including edible fruits) in- the body to optimize the cell and tissue levels which led to possible terfere with the SARS-CoV glycoprotein during the initial entry and benefits for the preventive measures for this pandemic COVID-19 viral release into the host cell which piloted the further research on situation. anti- SARS-CoV activity and anti-COVID-19 therapies using these The use of dietary supplements from various food sources and plant lectins (Keyaerts et al., 2007). Similarly, we hypothesized that nutraceuticals as coadjutant therapeutics for the prevention and EFCs may improve the immune system thereby suppress the COVID treatment of COVID-19 infection could be a useful strategy, since 19 infection, since antioxidants present in EFCs such as vitamin A, food-derived antioxidants has a key role in prevention of oxidative C, D, and E are reported to improve the immune response against stress and inflammation which are plays a significant cause in the COVID-19 (Khanna et al., 2021). progression of COVID-19 (Lammi & Arnoldi, 2021). The results of the The overall recommendation of EFCs in COVID-19 treatment is recent studies also suggested that antioxidant rich vitamins like vi- due to their ability to improve the immune system as well as reduc- tamin C and D are effectively activated the immune response which ing the oxidative stress in the host cell machinery which helps to leads to reducing the risk of respiratory tract infections by notice- prevent the viral entry. As reported earlier, seasonal epidemics with ably balancing the inflammatory reaction which suggests the use of 12 of 16 | SANTHI eT Al. F I G U R E 3 Possible binding mechanism of constituents of edible fruit extracts against the COVID-19 virus. The figure depicts the regular intake of edible fruits and their constituents/compounds leads to strengthening the immune cells and reduces the oxidative stress in the host body system which in turn inhibits the viral attachment and replication on the host cell those vitamins as nutritional supplements for COVID-19 patients AU T H O R C O N T R I B U T I O N S (Lammi & Arnoldi, 2021). Data curation; Formal analysis; Writing-original draft: V.P. Santhi. Despite a few vaccines available against Covid-19 and several Conceptualization; Writing-original draft: P. Masilamani. Formal analysis; vaccines in the pipeline, psychological stigma against this viral infec- Resources; Writing-original draft: Venkatraman Sriramavaratharajan. tion remains the same which warrants extensive research on herbal Data curation; Formal analysis; Writing-review & editing: Ramar medications in the cure of Covid-19. The current situation led the sci- Murugan. Data curation; Validation; Writing-review & editing: entists to develop new drugs and immune-modulators from natural Shailendra S. Gurav. Data curation; Formal analysis; Methodology: resources which reveal promising efficacy to promote immune sys- V.P. Sarasu. Data curation; Resources: S. Parthiban. Conceptualization; tem in the treatment and management of Covid-19. These continuing Funding acquisition; Project administration; Supervision; Validation; researches on preclinical and clinical trials on nutraceuticals and food Writing-review & editing: Muniappan Ayyanar. supplements of various plant resources could provide novel drugs against the emerging viral infections with better therapeutic bene- E T H I C S A P P R OVA L fits, less expensive, and minor adverse reactions. Considering the in- The manuscript is a review article and do not need any ethical creasing threat of COVID-19, it is opined to examine the therapeutic approval. efficacy of existing antiviral molecules of edible fruits discussed in this review as food supplements. Such focused research may provide ORCID prophylactic and adjuvant therapy against the COVID-19 because Muniappan Ayyanar https://orcid.org/0000-0003-4685-6376 of their potential antioxidant, anti-inflammatory and immunemodulatory effects against the other emerging viral infections. C O N S E N T FO R P U B L I C AT I O N The manuscript does not have any data copied from other sources and the mechanism flowchart provided in the manuscript is drawn by us. C O N FL I C T O F I N T E R E S T The authors declared that they have no conflict of interest. REFERENCES Abdul Ahmad, S. A., Palanisamy, U. D., Tejo, B. A., Chew, M. F., Tham, H. W., & Syed Hassan, S. (2017). 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Therapeutic potential of phytoconstituents of edible fruits in combating emerging viral infections

Therapeutic potential of phytoconstituents of edible fruits in combating emerging viral infections

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