Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review

SAJB-02501; No of Pages 11 South African Journal of Botany xxx (2019) xxx

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Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review D. Biswas a, S. Nandy a, A. Mukherjee b, D.K. Pandey c,⁎, A. Dey a,⁎ a b c

Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, India MMHS, South 24 Pgs, West Bengal, India Department of Biotechnology, Lovely Faculty of Technology and Sciences, Lovely Professional University, Phagwara, Punjab, India

a r t i c l e

i n f o

Article history: Received 26 March 2019 Received in revised form 12 July 2019 Accepted 29 July 2019 Available online xxxx Edited by NE Madala Keywords: Medicinal plant Moringa oleifera Antiviral activity Viral targets Clinical trials

a b s t r a c t Frequent use of medicinal plants is common in healthcare needs of mankind since ancient ages. Among these Moringa oleifera Lam. is one of the vastly used plant whose various parts (leaf, fruit, seeds etc.) are included in regular diet for their multiple ability of combating several health issues. WHO has highlighted on the proper utilization of natural products and marked plant-based medicines as prime study candidates. Taking initiative to explore bioactive leads other than conventional chemotherapeutic agents (with undesirable side effects) have drawn attention of the scientists involved in viral research due to the lack of effective vaccines and insufficient supply of existing costly drugs to socio-economic demands. Several studies were reported regarding the antiviral activity of M. oleifera plant, a pronounced bioprospective aspirant. The plant is known to be used in many traditional medicines and pharmacopeias against an array of medical conditions that include malaria, diabetes, skin infection, tuberculosis, anemia, headaches, epilepsy, sexually transmitted diseases and so on. In African traditional medicine, the plant is popularly used against AIDS and related secondary infections associated with HIV. It showed significant activities against viruses like HIV, HSV, HBV, EBV, FMDV and NDV. In some cases active molecules with mode of actions were documented by authors. On the other hand, there is a number of reports where neither lead compounds nor the relevant mechanisms were clarified regarding the viral inhibitory activities of crude plant extract. Immense studies should be going on to resolve those unanswered motifs along with the well planned trials of clinical application of already discovered potent phytochemicals. For conducting the continuous investigational groundwork in this field, the respective plant should be preserved with proper maintenance, necessarily. © 2019 SAAB. Published by Elsevier B.V. All rights reserved.

1. Introduction Plants are rich source of secondary metabolites and have been used for a variety of therapeutic purposes since the early days of human civilization. From ancient time to modern era of research, plant-derived natural moities have shown great contribution in the field of treating several ailments with their pharmaceutical potentials. Moringa oleifera Lam. (Moringaceae), commonly known as “drumstick tree,” an important medicinal plant belongs to the family Moringaceae under the order Brassicales, is widely distributed and cultivated throughout the tropical and subtropical region of South Asia, especially in Indian subcontinent. Various parts of this perennial, soft wood plant have long been used for the malnutrition, weakness in pox, antipyretic, diuretics, antioxidants, anti-inflammatory, anti-diabetic etc. in traditional healing practices. Moringa oleifera is one plant used in both ancient systems of medicine such as Ayurveda and the Chinese ancient medicinal system ⁎ Corresponding authors. E-mail address: [email protected] (A. Dey).

(Flora and Pachauri, 2011). Ayurveda advocates its use for pain relief and rapid expulsion of worms (Khan and Balick, 2001). In Ayurveda, the leaves of the plant are rubbed on a flat stone with water is being added gradually (Rathi et al., 2006). Traditional African diet recognizes the leaves, pods, seeds and flowers of the plant as prolific source of nutrition as well as “Miracle Tree” against a number of chronic human diseases (Matic et al., 2018). The plant is known as Haritashaaka, Raktaka and Akshiva in Ayurveda and as Sahajan in Unani system of medicine (Paikra et al., 2017). Several years ago, small pox (caused by Variola major and Variola minor) and chicken pox (caused by Varicella zoster) infections used to transmit in human in a higher rate with painful symptoms like high fever, reddish skin rashes, loss of appetite with severe weakening of nervous system. Once upon a time, M. oleifera seeds and flowers were used for those affected individuals, commonly in some regional culture, to push forward immunity development against these type of sufferings. Various parts of this plant have the traditional use in skin problem (leaves, seeds, root, gum), nervous disorder (leaves, flower, root, bark, gum), immunity imbalance (seeds) etc. as cited in literature (Kuben

https://doi.org/10.1016/j.sajb.2019.07.049 0254-6299/© 2019 SAAB. Published by Elsevier B.V. All rights reserved.

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

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and Roger, 2016). Scientific reports did not highlight on its direct effect on small pox or chicken pox, formally. Research is not going on regularly on small pox at present because WHO has declared the world as free from small pox infection in May, 1980 as no record found about the affected person after last patient of the respective disease was marked in Somalia in 1978 (WHO, 1980). Severity of chicken pox is now manageable with antiviral drugs of acyclovir group and effective vaccine was invented a few years ago. In this field, research can be continued on this plant to discover an alternative remedial measure. Presently, even in well-developed countries, research on this medicinal plant has received considerable interest due to its different promising bioactivities viz., hepatoprotective (Farooq et al., 2012), antibacterial (Abraham et al., 2014; Rahman et al., 2009), antifungal (Ganie et al., 2015; Patel et al., 2014), anti-cancerous (Abd-Rabou et al., 2017; Al-Shahrani et al., 2015), anti-inflammatory (Faizal et al., 2014) etc. as cited in several literatures. Being a good repository of antioxidants (Vats and Gupta, 2017), M. oleifera plant might be included in regular dietary supplement for the utilization of its ROS scavenging activity needed for faster recovery from pathogen related issues promoted through overproduction of oxidants in human body and effect of ROS in immune system in the advent of resistant strains. WHO also have declared the necessity to embrace a systematic approach for the evaluation of phyto-constituents as important resources in generating effective and affordable therapeutic agents with negligible toxicity (WHO, 2005). WHO is now emphasized on the regulation and policy development for the inclusion and validation of the use of Table 1 Traditional medicinal uses of Moringa oleifera against various medical conditions. Locality of use

Used against

References

Guatemala

skin, digestive, respiratory and joint diseases Arthritis, diabetes, fever, asthma, epilepsy, wound, body pains and weakness, cough, blood pressure, skin infection, chronic anemia, cancer, malaria and hemorrhage Diarrhea, toothache

Cáceres et al. (1991) Popoola and Obembe (2013)

Diabetes, anemia, high blood pressure

Abe and Ohtani (2013) Semenya et al. (2012) Sivasankari et al. (2014)

Nigeria

Nhema communal area, Zimbabwe Batan Island, the Philippines Limpopo Province, South Africa Thoppampatti, Dindigul district, Tamilnadu, India Ogbomoso, Southwest Nigeria Ibadan, Nigeria

Diabetes mellitus Cardiac, circulatory stimulant, antipyretic, anthelmintic, antiparalytic Malaria Sexually transmitted infections

Kimboza forest reserve in Morogoro, Tanzania Rwanda

Skin diseases, headache, detoxification, rheumatism, inflammation

Tirunelveli hills of Western Ghats, India Niger State, Nigeria

To increase sperm production

Sokoto, Northwest Nigeria India and other parts of South Asia

India, Africa

Voluntary depigmentation

Tuberculosis and other respiratory diseases Diabetes

traditional herbal medicines in national health care systems, simultaneously (WHO, 2013). Ethnobotanical information have provided a better opportunity of finding active leads easily than that of random screenning. Therapeutic principles of traditional medicinal plants were found to be efficient in yielding potent antiviral drug molecules and offered themselves for scientific evaluationowing to the high cost and undesirable side effects of conventional antiviral drugs, absence of effective vaccines (in some cases) and emergence of resistant strains. Moringa oleifera plant possesses remarkable inhibitory activities against viruses like HIV (Nworu et al., 2015), HSV (Goswami et al., 2016), HBV (Feustel et al., 2017), EBV (Murakami et al., 1998), FMDV (Imran et al., 2016) and NDV (Okwor et al., 2013) according to the reports of some authors. The objective of the review is to focus mainly on the potential antiviral efficacy of this plant along with some brief ideas about the respective viruses, epidemiology and conventional therapy till date. Besides it also presents the traditional use of this popular medicinal plants as an antiviral agent and also against AIDS and related secondary infections associated with HIV especially in the vast areas of the Africa. Table 1 presents traditional medicinal uses of M. oleifera against other medical conditions and Table 2 presents the traditional use of the plant as antiviral agent especially against HIV/AIDS and related secondary infections associated with HIV.

2. Methodology Scientific search engines such as Medline, Google Scholar, PubMed, Pubget, Scopus, ScienceDirect, SpringerLink, Highware, Mendeley, EMBASE, JSTOR were critically searched to obtain papers with the help of search strings viz. “Moringa oleifera,” “Moringa oleifera antiviral,” “Moringa oleifera HIV/AIDS/HSV/HBV/EVB/FMDV/NDV,” “Moringa oleifera traditional,” “Moringa oleifera ethnobotany” etc. Crossreferencing among the obtained papers also retrieved a total number of 73 publications from 1980 to 2018 which are cited in the present work. The paper compiles the use of M. oleifera against 6 different viruses investigated in 14 research papers. Information presented in this

Maroyi (2011)

Olorunnisola et al. (2013) Gbadamosi (2014) Amri and Kisangau (2012) Kamagaju et al. (2013) Ayyanar and Ignacimuthu (2011) Mann et al. (2007) Shinkafi et al. (2015) Morimitsu et al. (2000)

Inflammation, infectious diseases, gastrointestinal, hematological, cardiovascular and hepatorenal disorders, tumors, headache, Gopalakrishnan Syphilis, malaria, skin diseases, bronchitis, pneumonia, liver and spleen et al. (2016) problems, joint pain, diarrhea, headaches, epilepsy and sexually transmitted diseases, scurvy, gout, cramp

Table 2 Traditional use of Moringa oleifera as antiviral agent especially against HIV/AIDS and related conditions. Locality of use

Used against

References

Nigeria

HIV/AIDs infections

Southern Benin

Nutritional powder to the persons living with HIV/AIDS HIV/AIDS-related opportunistic infections

Popoola and Obembe, (2013) Agoyi et al. (2014) Chinsembu and Hedimbi (2010)

Katima Mulilo, Caprivi region, Namibia Uganda Keffi Metropolis, Nigeria Western Uganda North-west Cameroon Katima Mulilo, Caprivi region, Namibia Jos, Plateau state, Nigeria Uganda Zimbabwe Jos, Plateau state, Nigeria

HIV/AIDS and related conditions HIV/AIDS opportunistic infections Boost appetite/immunity (management of HIV/AIDS opportunistic ailments) Diarrhea, skin infections, vomiting (management of HIV/AIDS opportunistic ailments) Diarrhea, skin infections, vomiting (management of HIV/AIDS opportunistic ailments) Antiviral (hepatitis) HIV/AIDS and related conditions To boost the immune system in HIV/AIDS patients Viral infections

Lamorde et al. (2010) Mustapha (2014) Asiimwe et al. (2013) Noumi and Manga (2011) Chinsembu and Hedimbi (2010) Ohemu et al. (2014) Lamorde et al. (2010) Monera et al. (2012) Ohemu et al. (2014)

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

D. Biswas et al. / South African Journal of Botany xxx (2019) xxx

review may be used for basic and clinical research on the antiviral efficacy of M. oleifera in future. 3. Brief idea about viruses inhibited by M. oleifera Documentation of previous reports have said that the plant M. oleifera (Moringaceae) showed inhibitory activity principally against a few infectious disease causing viruses viz., (A) Human Immunodeficiency Virus (HIV), causative agent for Acquired Immune Deficiency Syndrome (AIDS) in human; (B) Herpes Simplex Virus (HSV) causes fever blisters or cold sores around the mouth and lips and genital infection in human body; (C) Hepatitis B Virus (HBV) which affects human liver and causes inflammation, cirrhosis and liver cancer; (D) Epstein– Barr Virus (EBV) responsible for various non-malignant, premalignant and malignant lymphoproliferative diseases in human; (E) Foot-andMouth Disease Virus (FMDV) causes blisters in mouth and feet of human and some hoofed animals; (F) Newcastle Disease Virus (NDV) affecting avian species and transmissible to human through poultry birds (Swayne and King, 2003). A little information of those viruses are given below: 3.1. HIV Human Immunodeficiency Virus (HIV) is a positive sense, singlestranded, enveloped, RNA virus belongs to the Retroviridae family. It causes AIDS by attacking immune system of the human body. Gradual disruption of immunological balance of human body is initiated through the killing of immune cells by HIV and this favors an increase of viral load in blood. HIV infection is usually asymptomatic until it progresses to AIDS. AIDS symptoms include weight loss, fever, sore throat, fatigue, nausea, diarrhea, vomiting, shortness of breath, severe headache, joint pain, chronic cough etc. Severe weakening of immune system makes the body susceptible for other recurrent infection. If HIV is left untreated, even a minor infection may be fatal as the body is unable to fight off this. About 36.9 million people were living with HIV infection in 2017 and Swaziland was marked as most highly affected country (Joint United Nations and Programme on HIV/AIDS, 2018). On account of the introduction of “Highly Active Antiretroviral Therapy” (HAART) medical professionals were able to witness a notable drop in AIDS related deaths (Chesney, 2003). However, majority of the people is unable to access this prolonged therapeutic approach because of high expense and intolerable side effects.

Surface glycoprotein

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RNA genome of HIV is encapsulated with glycoprotein envelope which consists of two subunits named gp120 and gp41. Fusion of gp120 with the CD4 positive T cell of the host mediates a conformational change in gp120 and it ensures efficient interactions with cellular factors CCR5 and CXCR4. This results the viral entry into the host cell. After this, single-stranded RNA genome of HIV is reverse transcribed into double-stranded DNA molecule by reverse transcriptase and integrated into the host genome through the activity of integrase. Subsequent polyprotein processing takes place with protease for the maturation and proliferation of virion particles (Kirchhoff, 2013). Schematic representation is given in Fig. 1. Conventional drugs are applied to target different components of HIV life-cycle like lamivudin (reverse transcriptase inhibitor), elvitegravir (integrase inhibitor), ritonavir (protease inhibitor), nelfinavir (protease inhibitor), zidovudine (reverse transcriptase inhibitor), maraviroc (target CCR5, inhibits entry), enfuvirtide (target gp41), raltegravir (integrase inhibitor) etc. Emphasizing on combinatorial therapy World Health Organization (WHO) has recommended HAART for the better management of this fatal disease. 3.2. HSV Herpes Simplex Virus of Herpes viridae family consists of doublestranded linear DNA genome wrapped with lipid bilayer envelope. The outer envelope is attached with the capsid by means of a tegument. Entry of HSV into the host cell involves binding of two viral envelope glycoproteins called gC and gB with the heparin sulphate receptor of host cellular surface. Next, another glycoprotein gD binds specifically to at least one of the three known receptors viz., HVEM, nectin-1 and heparin sulphate. After binding, gD changes its conformation and interacts with gH and gL to form a complex. This interaction may result in hemifusion state and creation of entry pore takes place. Transcription of HSV genes is catalyzed by RNA polymerase II of host cell. Early gene expression of virus allows the synthesis of enzymes involved in DNA replication and the production of glycoproteins. Late gene expression of virus occurs last to encode proteins required for virion particle formation (Thellman and Triezenberg, 2017). These events are schematically presented in Fig. 2. HSV may persist in a quiescent but persistent form, mainly in neural ganglia. The rate of infection with HSV (1&2) is around 90%, worldwide. More than 3.7 billion people under the age of 50 years are infected with HSV-1 according to global estimate of WHO. In USA 22% of adults are noted to be HSV2-positive and in Europe the figure is around 15%

Cellular receptor Viral DNA

Interaction Integration of viral DNA into host DNA HIV

Transcription Processing

Viral transcript

Nucleus Host cell

Viral proteins Release of virus

Fig. 1. Infection mechanisms of different viruses against which Moringa oleifera and derived compounds showed promising antiviral activities. HIV infection mechanism.

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

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D. Biswas et al. / South African Journal of Botany xxx (2019) xxx

Adsorption

Membrane fusion Penetration

HSV

Tegument enters into cell

Nucleus Replication Genome uncoating

Viral release Assembly

Host cell Fig. 2. Infection mechanisms of different viruses against which Moringa oleifera and derived compounds showed promising antiviral activities. HSV infection mechanism.

(Gottlieb and Deal, 2017). Acyclovir, valacyclovir, famicyclovir etc. are commonly used as the medication for HSV infection. 3.3. HBV Hepatitis B Virus, a double-stranded DNA virus, classified under Hepadnaviridae, is one of the non-retroviral agent which uses reverse transcription as a part of its replication process. HBV initially binds to heparin sulphate proteoglycan of host cell surface and enters through

HBV

the endocytosis mediated by clathrin or caveolin-1. Release of nucleocapsid into the host cytoplasm takes place following endocytosis. For the multiplication of virus, its genomic DNA has to be transferred to the host cell nucleus. Thereafter, fully double-stranded DNA from partially double-stranded viral DNA is formed by the host DNA polymerase and subsequently it is transformed into covalently closed circular DNA (ccc DNA) which serves as a template for the transcription of four viral mRNAs. The largest mRNA is used to make new genome copies, capsid core protein and viral RNA-dependent-DNA-polymerase. Those

Receptors Core assembly and RNA packaging

V Viral release

Reverse transcription

Viral entry

Translation

(-) strand DNA

Nucleus

Maturation

(+) strand DNA

(+) RNA progenome

Short transcripts Viral surface proteins

cccDNA

Transcription Translation RNA Pol II Hepatocyte

Fig. 3. Infection mechanisms of different viruses against which Moringa oleifera and derived compounds showed promising antiviral activities. HBV infection mechanism.

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

D. Biswas et al. / South African Journal of Botany xxx (2019) xxx

four viral transcripts undergo additional processing to form progeny virions (Schädler and Hildt, 2009). A diagrammatic presentation is given in Fig. 3. Existing antiviral drugs like entecavir, tenofovir, lamivudine, adefovir, telbivudine etc. can help to fight with that virus and slow down its ability to damage liver. About 70–90% of the population becomes HBV-infected before the age of 40 years and 8–20% people are HBV carrier. Highly HBV affected areas include SE Asia, Pacific Basin, Amazon Basin, part of Middle East, the central Asian Republics and some countries in eastern Europe (WHO, 2002). 3.4. EBV Epstein Barr Virus which was formerly known as Human gamma herpes virus 4, is one of the life-threatening virus of Herpesviridae family, causes infectious mononucleosis, several lymphomas and some non-lymphoid malignancies. Genome of this enveloped viral particle consists of DNA double helix. EBV infects different types of cells including B cells and epithelial cells. Processes of entering into these two types of cells are different from each other. B cell entry is initiated with the binding of viral glycoprotein gp350 to host cellular receptor CD21 (or CR2). Then viral glycoprotein gp42 interacts with MHC II of host cell and this triggers the fusion of viral envelope with host cellular membrane allowing the viral entry into B cell. Another cellular factor CD35 (or CR1) provides a route for EBV entry into the CD21 negative cells, including immature B cells. EBV infection downregulates CD35 expression of host cells. Interaction between viral protein BMRF-2 and cellular β1 integrins mediates entry of EBV into the epithelial cells. Afterwards, viral protein gH/gL interacts with cellular αvβ6/αvβ8 integrins. Triggering the fusion of the viral envelope with the epithelial cell membrane that interaction allows epithelial-cell entry of EBV. Lytic cycle involves viral DNA polymerase for replication which results the production of infectious virion particles. Opposed to this, in latency circular EBV DNA remains in the cell nucleus as an episome and is copied through cellular DNA polymerase (Csween and Crawford, 2003). A comprehensive diagram is included here (Fig. 4). Infants become susceptible to EBV infection as soon as maternal antibody protection disappears. However, in childhood this infection is more or less asymptomatic. During adolescence, EBV causes infectious mononucleosis by 35–50%. Using chemotherapeutic agents like gancyclovir, cis-platinum, 5-fluorouracil, taxol etc. is a regular practice to lessen the deadly effects of the functional infection of EBV.

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3.5. FMDV Foot-and-mouth disease virus or Aphthovirus of Picornaviridae family possesses single-stranded positive encoding RNA genome without envelop. Binding of virus to host cellular receptor triggers a folding-in of the cell membrane. After the virion entrance, genome uncoating takes place and replication occurs. Next, translation occurs through a cap-independent mechanism by IRES (Internal Ribosomal Entry Site) element. Viral proteases inhibit the synthesis of normal cellular protein and viral proteins interact with different components of the cell. The infected cells become damaged by producing large quantities of viral RNA and capsid proteins which are prerequisite for the new virus assembly. This virus occurs in seven major serotypes viz., O, A, C, SAT-1, SAT-2, SAT-3, Asia-1 among which O is most common (Gao et al., 2016). Major events are depicted in Fig. 5. There is no specific treatment available for this disease. The disease symptoms are not so severe, only blisters with mild flu occurs. Common analgesics and antipyretics are often given to relieve sufferings.

3.6. NDV Newcastle Disease Virus or Avian avulavirus 1 falls under Paramixoviridae family, attacks mainly avian species and affects severely the poultry industries. Generally, this infection consists of signs like depression, diarrhea, prostration, edema, paralysis, torticollis and respiratory disorder in birds. NDV is spreadable primarily through direct contact between healthy birds and the bodily discharges of infected birds. Exposure of human beings to the infected birds (e.g. from poultry) can cause mild conjunctivitis and influenza-like symptoms. No treatment is available for NDV infection but prophylactic vaccines can reduce the likelihood of outbreaks. Antibiotics may assist to control secondary infection. NDV strains can be categorized into three types namely velogenic (highly virulent), mesogenic (intermediate virulence) and lentogenic (nonvirulent). Velogenic strains are responsible for severe nervous and respiratory signs, spread rapidly and cause upto 90% mortality. Mesogenic strains affect production and quality of eggs and results about 10% mortality. Lentogenic strains produce mild signs of infection with negligible mortality(Swayne and King, 2003). A diagram of the life-cycle of this enveloped, negative sense, single-stranded RNA virus is outlined in Fig. 6.

EBV infected plasma cell

EBV Viral replication

Epithelium Viral replication

EBV infected memory B cell

EBV infection of naive B cell

EBV infected germinal centre B cell EBV infected blast Cytotoxic T cell Fig. 4. Infection mechanisms of different viruses against which Moringa oleifera and derived compounds showed promising antiviral activities. EBV infection mechanism.

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

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D. Biswas et al. / South African Journal of Botany xxx (2019) xxx

Integrin receptor

FMDV

Host cell membrane inward folding (-ve)RNA synthesis

dsRNA intermediate

(+ve)RNA synthesis

Viral entry

Genome uncoating

Encapsidation

Nucleus

Translation Pentamer Non-structural proteins

Processing

Ribosome

Structural proteins Fig. 5. Infection mechanisms of different viruses against which Moringa oleifera and derived compounds showed promising antiviral activities. FMDV infection mechanism.

4. Antiviral potentiality of M. oleifera Efforts to develop alternative antiviral therapeutic agents with significant mode of action, acceptable toxicity and less resistant profile have generated interest to find out potential drug leads from bioactive natural compounds of plant origin. Unfortunately, it is hard to use traditional healers universally to the infectious diseases due to paucity of information. It necessitates enrichment of indigenous knowledge of medicinal plants based on ethnopharmacological data required in the

field of drug development approaches. Moringa oleifera is one of the important medicinal plant possessing an indicative number of biochemical compounds according to GC–MS analysis (Aja et al., 2014). Compounds like L-ascorbic acid, oleic acid, 9-octadecenoic acid, phytol, N-(-1-methylethyllidene) benzene ethanamine, 3, 4-epoxy-ethanone, 4-hydroxy-4-methyl-2-pentane, 3-ethyl-2,4-dimethyl-pentane, 1hexadecanol, octadecamethyl–cyclononasiloxane, hexadecanoic acid, 3,5-bis (1,1-dimethylethyl)-phenol etc. found in this plant extract should be considered for proper screening of antiviral potential,

Viral entry

Replication NDV

(-) Genome

(+) Antigenome

Transcription

Replication

Transcription Cap Cap Cap

AAA AAA AAA

(-) Genome

Translation

Attachment proteins

Host cell

Matrix protein

Capsid proteins

Nucleus Budding and viral release

Fig. 6. Infection mechanisms of different viruses against which Moringa oleifera and derived compounds showed promising antiviral activities. NDV infection mechanism.

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

D. Biswas et al. / South African Journal of Botany xxx (2019) xxx

separately. It is noteworthy that the plant M. oleifera (Moringaceae) showed remarkable inhibitory activity specifically against six different viruses as reported by several authors. Relevant information obtained from their study are presented in Table 3 which summarizes the inhibitory activity of M. oleifera extracts and compounds against six different viruses with notes on their mode of action. Fig. 7 represents the chemical structures of the antiviral compounds derived from the plant.

4.1. HIV inhibitory activity Being rich in vitamin and other nutrients including β-carotene, potassium, calcium, magnesium, sulfur and phosphorus with a good safety profile,the extract of M. oleifera plant is generally advocated to HIV patients along with anti-retroviral therapy as a nutritional supplement and immune booster. Thirty-three HIV patients were screened after supplementation of M. oleifera leaf powder along with the medication of nevirapin, a commonly used antiretroviral drug (Monera et al., 2012). Since the safety profile of nevirapine is not affected by Moringa oleifera when co-administered to HIV-infected patients, this well-tolerated combinatorial therapy may be applied, frequently. The inhibitory activity of three different extracts of M. oleifera on lentiviral vector infectivity was studied in HeLa cell lines in vitro (Nworu et al., 2015). Here, each of the extracts were active against HIV lentiviral vector and inhibited early events of viral replication in certain concentrationdependent manner. Aqueous extract, methanolic extract and petroleum ether extract of M. oleifera leaf have shown EC50 values of 7.17, 7.72 and 7.59 μg ml−1, respectively. Bioactivities may be attributed to the contents of saponins, alkaloids, glycosides, tannins, carbohydrates, flavonoids, resins, acidic compounds and proteins present in the leaf extract. Tshingani et al. (2017) have selected 60 HIV-infected patients at the stage of clinical trial II for their study. Among them 30 randomly chosen patients were given 30 g of M. oleifera leaf powder (an amount of 10 g thrice) daily over six months and the rests were kept as control providing nutritional counseling only. After this six months follow-up, the patients consuming M. oleifera leaf powder exhibited a significant increase in body mass index and amount of albumin in blood as compared with the control ones (Tshingani et al., 2017). Comparative study of the steady-state pharmacokinetics between two synthetic drugs, nevirapin and efavirenz was done before and after supplementation with M. oleifera leaf powder in HIV positive people. Here, 19 HIVaffected people were studied thoroughly to examine the impact of

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phytotherapy (Sebit et al., 2000). The informative data obtained from their report have supported the role of phytotherapy in improving the quality of life of HIV-I-infected patients, significantly. In silico study based on ligand–receptor binding i.e. molecular docking is an innovative approach to determine the interaction between drug leads and viral proteins based on dock pose analysis prior to in vitro experimentation. It may be utilized as a guideline through the view of reducing unnecessary expenditure in random “wet lab” screening methods. An attempt has been made by Sangar et al. (2015) for detecting the role of M. oleifera in HIV treatment using CXCR4 as a target receptor. Docking was done using Autodock 4 software for the analysis of 18 selected phyto-constituents of this plant (Sangar et al., 2015). On the basis of docking score analysis ellagic acid and aurantiamide acetate may be considered as promising candidates against CXCR4 receptor among 18 test compounds. Further extensive study should be continued to explore unique anti-HIV activity of this plant in vitro and in vivo and potential bioactive lead molecules.

4.2. HSV inhibitory activity Drumstick (M. oleifera), as a wholesome for HSV infected individuals is included in primary healthcare system since a long ago. Researchers have observed the direct effects of this plant on HSV strains through several in vitro experiments. Aqueous extract of M. oleifera inhibited HSV type 1 & type 2 by 43.2% and 21.4%, separately at the concentration of 200 μg ml−1(Rosmarinus et al., 2017). Compounds like dibutyl phthalate, 4-dodecanol, hentriacontane, squalene, tetracontane-1,40diol, alpha tocopherol, beta amyrin etc. present in plant extract may be responsible for mediating that promising antiviral potentiality, likewise. Crude ethanolic extract of M. oleifera leaves attenuated the activity of HSV-1, specifically with EC50 value of 100 ± 5.3 μg ml−1which was found in an authentic document (Li et al., 2018). Aqueous extract of M. oleifera leaves activated cellular immunity in HSV-1 infected mice by reducingtheviral load and related skin lesion as reported by Yoshida et al. (2016). Their HPLC analysis have confirmed the presence of myricetin, apigenin and chrysin as flavonoid constituents having the probable ability to hinder viral growth (Yoshida et al., 2016). According to the report of Pramyothin et al. (2003) it is evident that water and ethanolic extract of M. oleifera have shown significant prophylactic activity by inhibiting more than 50% of plaque formation of Herpes Simplex Virus type 1 (HSV-1) at a measurable dose of 100 μg ml−1

Table 3 Summary of the inhibitory activity of Moringa oleifera against six different viruses. Name Types Plant Solvent/chemicals compounds of virus of strain part used

Mode of action

EC50 (μg ml−1)

CC50 (μg ml−1)

Reference

HIV

1

Leaves

7.17, 7.72, 7.59

1&2

Leaves

41.58, 38.88, 32.33 ≥200

E et al., (2015), Sangar et al. (2015)

HSV

Inhibited viral replication Taergeted CXCR4 Activated cellular immunity; Hindered viral growth

HBV

C&H

Leaves

≈45–50

≤500

Feustel et al. (2017), Waiyaput et al. (2012)

EBV

–

Leaves, Seeds

32.7, 35.3, 27.9, 13.0

≥100

Murakami et al. (1998), Maoka et al. (1999)

FMDV

–

Leaves

Ethanol, Methanol 4-(α-L-rhamnosyloxy)benzyl isothiocyanate, niazimicin, β-sitosterol-3-O-β-D-glucopyranoside, niaziminin Chloroform, Ethanol

Decreased HBsAg, CTGF, TGF-β1, IL-6, cccDNA; Increased CAT expression Showed inhibitory activity against EBV-EA activation

≤50

≥100

Younus et al. (2016)

NDV

–

Leaves

Methanol

Targeted protein/enzymes of viral replication cycle Immune booster

Water, Methanol, Petroleum ether Ellagic acid, aurantiamide acetate Water, Ethanol aurantimide acetate, benzyl isothiocyanate, chlorogenic acid, benzyl glucosinolate, quercetin, moringinin, niazimicin, niaziminin, apigenin, chrysin, myricetin, pterygospermin, dibutyl phthalate, squalene, alpha- tocopherol, beta amyrin Water, 80% hydroalcoholic solvent, 50 mM Tris–HCl buffer(pH 7.5)

100, 100 ± 5.3, 74.8 ± 4.7

(Rosmarinus et al. (2017), Li et al. (2018), Pramyothin et al. (2003), Goswami et al. (2016), Yoshida et al. (2016)

Not Not Okwor et al. (2013), Eze et al. determined determined (2014)

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

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D. Biswas et al. / South African Journal of Botany xxx (2019) xxx

Ellagic acid

Benzyl isothiocyanate

Chrysin

Aurantiamide acetate

Dibutyl phthalate

Myricetin

Benzyl glucosinolate

Pterygospermin

Quercetin

β-amyrin

Apigenin

Chlorogenic acid

Fig. 7. Bioactive compounds obtained from Moringa oleifera.

(Pramyothin et al., 2003). Goswami et al. (2016) reported that the methanolic extract of M. oleifera leaves exhibited discernible inhibitory activity against HSV-1 with EC50 value of 74.8 ± 4.7 μg ml−1at noncytotoxic concentration (Goswami et al., 2016). They have isolated several phytochemicals like aurantimide acetate, benzyl isothiocyanate, chlorogenic acid, benzyl glucosinolate, quercetin, moringinin, niazimicin, niaziminin, pterygospermin etc. for the elucidation of the bioactive potency of that plant in future. 4.3. HBV inhibitory activity This hepatotropic virus is culpable for several liver functions impairment and eventual development of hepatocellular carcinoma. International guidelines have stated about the long term administration of antiviral drugs to reduce the severity of infection and histological improvement. Normalization of liver function is not achieved very frequently through the conventional chemotherapy. Intended to hunt alternative therapeutic strategy scientists are interested to employ plant source at present. Feustel et al. (2017) examined the effect of M. oleifera aqueous leaf extract in transfected Huh7 cells expressing C and H genotypes of HBV strains. The HBsAg secretion in the supernatant of transfected Huh7 cells with genotypes C and H of HBV was decreased independently with M. oleifera treatment. CTGF and TGF-β1gene expression were decreased also in comparison with the control ones. Transfection of those cells with both HBV genotypes strongly decreased CAT expression, which was restored with M. oleifera treatment, conspicuously. Moringa oleifera treatment reduced the IFNβ1 gene expression slightly higher in genotype H than that of genotype C. After treating with M. oleifera, IL-6 showed a tendency to decrease in a dosedependent manner in the supernatant of Huh7-transfected cells with genotypes C and H, positively (Feustel et al., 2017). Waiyaput et al.

(2012) prepared two types of M. oleifera extracts using two different solvents viz., 80% hydroalcoholic solvent and a 50 mM Tris–HCl buffer (pH 7.5) and evaluated HBV inhibitory effect of the respective plant in COS-7 and HepG2 cell lines through several laboratory experiments. Hydroalcoholic extract of M. oleifera drastically decreased the level of cccDNA in transiently transfected HepG2 cells. Tris–HCl buffer (pH 7.5) extracts of M. oleifera also showed anti-HBV activity with a mild cytotoxicity (Waiyaput et al., 2012). These promising results are needed to be analyzed further along with isolation of phytochemicals and molecular identification of viral targets, meticulously. 4.4. EBV inhibitory activity Once the establishment of successful infection of EBV, it takes 4– 6 weeks to show up symptoms including fatigue, fever, lack of appetite, skin rash, sore throat, swollen glands in the neck, weakness and sore muscle, commonly. Transmission of EBV mainly occurs through intimate saliva contact in infectious stage. In addition, passing through the placental barrier this virus may infect fetus in infected pregnant woman when reactivated during its post latency stage. In severe cases no antiviral drugs or vaccines work effectively in stoppage of viral build out within human body. Attempt to develop functional remedy have generated interest within researchers to study the natural products in this regard. Maoka et al. (1999) isolated seven biochemical compounds from ethanolic extract of M. oleifera seeds. These are the followings: (i) O-ethyl-4-(α-L-rhamnosyloxy) benzyl carbamate, (ii) 4-(α-L-rhamnosyloxy) benzyl isothiocyanate, (iii) niazimicin, (iv) niazirin, (v) β-sitosterol, (vi) glycerol-1-(9-octadenoate), (vii) 3-O(6′-O-oleoyl-β-D-glucopyranosyl)-β-sitosterol and (viii)β-sitosterol-3O-β-D-glucopyranoside. All the compounds were tested for their inhibitory effects on Epstein–Barr virus-early antigen (EBV-EA)

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

D. Biswas et al. / South African Journal of Botany xxx (2019) xxx

activation in Raji cells induced by the tumor promoter, 12-Otetradecanoyl-phorbol-13-acetate (TPA). Each of these showed considerable inhibitory activity against EBV-EA activation whereas compounds (ii), (iii) and (viii) have given remarkable results with EC50 values of 32.7, 35.3, 27.9 μg ml−1, respectively without exhibiting any significant cytotoxicity (Maoka et al., 1999). Murakami et al. (1998) isolated three compounds viz., niazimicin, niaziminin, 4-(4′-O-acetyl-α-Lrhamnosyloxy) benzyl isothiocyanate from the metanolic extract of M. oleifera leaves. Among these onlyniaziminin (a thiocarbamate) showed significant inhibition against EBV activation in Raji cells. They have stated that only one acetyl group should be present compulsorily at the oxygen of the 4′-position without the presence of any other acetyl group to the remaining hydroxyl groups of the sugar moiety of this compound (Murakami et al., 1998). Detailed investigation of the activities of prospective lead molecules is needed for the proper utilization of the medicinal value of M. oleifera regarding various target inhibition of this deadly virus. 4.5. FMDV inhibitory activity Spreading of highly contagious foot mouth disease occurs through infected individuals plus aerosol transmission within human and hoofed livestock. Most of the countries are now trying to invent progressive control pathway for this disease outbreak cost effectively. They are interested to utilize effectual bioactive plant products in lieu of applying hazardous chemotherapeutic strategies. Younus et al. (2016) carried out MTT colorimertic assay to evaluate antiviral and cytotoxic activity of chloroformic extract of M. oleifera leaves in diminishing FMDV infection in BHK-21 cell line. Concentration of the respective plant extract ranges from 1 to 50 μg ml−1 have indicated significant activity in comparison with the rests. Observing this, the authors have recommended for future studies aiming to elucidate the mode of action of this inexpensive and easily available plant resource (Younus et al., 2016). Imran et al. (2016) prepared ethanolic extract of M. oleifera plant and diluted with M-199 cell culture media and then performed MTT colorimetric assay using BHK-29 cell line. The plant extract showed considerable antiviral activity against FMDV at concentration ranges of 50–300 μg ml−1and revealed cytotoxicity at higher concentration (100 μg ml−1) (Imran et al., 2016). Investigational research should be continued to develop efficient, less resistant, low cost and easily available bioactive product against FMDV. 4.6. NDV inhibitory activity In 1926, the first outbreaks of Newcastle disease occurred in chickens in Indonesia and England and NDV was recognized as the etiologic agent (Swayne and King, 2003). It is a serious threat for poultry industry due to high mortality rate. It is essential to block the spreading of this disease as early as possible to reduce economic loss. Being a multipurpose medicinal plant, M. oleifera have drawn attention of researchers in arresting the epidemic of Newcastle disease. Okwor et al. (2013) investigated the effects of crude methanolic extract of M. oleifera in chickens experimentally challenged with velogenic Newcastle Disease Virus. They randomly divided experimental birds into four equal groups of 30 chicks where groups I and II were treated orally with 200 mg kg−1 body weight of the plant extract daily for two weeks, groups II and III were vaccinated and group IV was kept untreated. Moringa oleifera extract increased Newcastle Disease Haemaagglutination Inhibition titer as well as the total and differential leukocyte counts in the treated and unvaccinated group I birds much more than those of treated and vaccinated group II. Henceforth, this plant extract may be recommended as an immune-booster in non-vaccinated birds to fight against the lethal infection (Okwor et al., 2013). Comparative study was performed by using the plant extract plus vaccination and Vacci-Boost supplementation with vaccination, separately in different group of chicken birds. In both ambiences immune response was

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improved in birds, significantly (Eze et al., 2014). From the above-mentioned observations, it can inferred that large scale use of M. oleifera supplement along with vaccination against NDV might be possible after in-depth investigational study. 5. Discussion A number of bioactive compounds obtained from M. oleifera plant are waiting to be evaluated for potential antiviral activities and for the discovery of the mode of action, accordingly. Massive experimental studies are needed to be carried out for genuine utilization of those phytochemicals. Those compounds should be evaluated against other similar type of viruses to inspect their diverse activities. Moreover, efficacy of those compounds in vivo may not be matched with the procured outcome of in vitro experimentation because of body's own metabolism system which is totally different from laboratory condition. Frequent animal model based studies following proper guidelines are necessary as per the requirement for clinical trials of prospective natural products. No clinical study has been recorded in order to authenticate the promising antiviral efficacy of the plant. The only clinical study using M. oleifera was performed to evaluate its anti-asthmatic activity which revealed its safe and efficacious applications on human samples (Agrawal and Mehta, 2008). However, the detailed clinical and experimental trials are needed to investigate its underlying mode of action and therapeutic ability especially as an antiviral agent. Moreover, no structure activity relationship studies have been carried out to elucidate the role of M. oleifera phytochemicals as antiviral agents. More clinical studies are necessary to find out the necessity and feasibility to generate synthetic antiviral drugs using Moringa derived natural compounds as template. After authentic validation of experimental studies it might be possible to use the plant constituents universally in treating incurable viral diseases including the de novo development of promising drugs. According to the report of World Health Organization (WHO), the use of natural bioactive compounds throughout the world now exceeds by two to three times higher than that of conventional drug candidates (WHO, 2013). The great demand for plant-based medicinal compounds has been developed because of their wide biological activities, high safety and lesser cost. Their global market currently stands at over $ 60 billion annually (Gunjan et al., 2015). Lack of ethnomedicinal information, insufficient knowledge of plant metabolites, problem of obtaining large-scale supply of promising plant-derived compounds and lack of necessary funding have made great challenges to face. Proper survey of botanically rich areas, improvement of tissue culture methods for growing medicinally important plants and involvement of much more funding agencies in multidisciplinary analytical research are essential regarding these issues to address the necessity of prospective bioactive plant compounds in drug development approaches. 6. Conclusion Medicinal properties of M. oleifera plant possess a long history of uses because of better tolerance, low cost and easy availability in countries like India which have good agricultural condition and rich regional distribution of that plant. Now, the plant has become an indispensable part of public healthcare throughout the world. Various survey reports have highlighted on its widespread uses. However, reckless utilization of this plant resource may threaten its sustainability. It is necessary to preserve this important plant as soon as possible for further uses. Clonal propagation may be a useful tool for the regeneration of required plant parts possessing expected antiviral activities. Abuses like grazing, deforestation and other destructive human activities in the respective area should be stopped through making laws with respective rules and recommendations. To avail medicinal benefits from this enriched plant resource, research activities should be encouraged by regional, national and international funding and other necessary supportive activities. Besides, rigorous pre-clinical and clinical trials and elucidation of

Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049

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structure–activity relationships of the compounds obtained from the plant are needed to assess the druggability of the natural templates and also to better understand the underlying mechanism of action of antiviral properties of this potent ethnomedicinal plant.

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Please cite this article as: D. Biswas, S. Nandy, A. Mukherjee, et al., Moringa oleifera Lam. and derived phytochemicals as promising antiviral agents: A review, South African Journal of Botany, https://doi.org/10.1016/j.sajb.2019.07.049