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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 53
| Issue : 5 | Page : 403-411 |
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Demystifying therapeutic potential of medicinal plants against chikungunya virus
Sukender Kumar1, Chanchal Garg1, Samander Kaushik2, Harpal Singh Buttar3, Munish Garg1
1 Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India
2 Center for Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India
3 Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| Date of Submission | 28-Apr-2020 |
| Date of Decision | 20-Apr-2021 |
| Date of Acceptance | 28-Aug-2021 |
| Date of Web Publication | 24-Nov-2021 |
Correspondence Address:
Prof. Munish Garg
Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak - 124 001, Haryana
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.IJP_81_20
Viral infections are posing a great threat to humanity for the last few years. Among these, Chikungunya which is a mosquito-borne viral infection has produced enormous epidemics around the world after been rebounded. Although this infection shows a low mortality rate, patients suffer from fever, arthralgia, and maculopapular rashes, which reduce the quality of life for several weeks to years. The currently available treatments only provide symptomatic relief based on analgesics, antipyretics, and anti-inflammatory drugs which are nonspecific without satisfactory results. Medicinal plants are a widely accepted source of new molecules for the treatment of infectious diseases including viral infections. The scientific reports, primarily focusing on the anti-chikungunya activity of plant extracts, natural origin pure compounds, and their synthetic analog published from 2011 to 2021, were selected from PubMed, Google Scholar, and Scopus by using related keywords like anti-chikungunya plants, natural antivirals for Chikungunya. The present review decodes scientific reports on medicinal plants against chikungunya virus (CHIKV) infection and demystifies the potential phytoconstituents which reveals that the screening of flavonoids containing plants and phytochemicals showing efficacy against other arbovirus infections, may prove as a potential lead for drug development against CHIKV. The present article also outlines pathogenesis, clinical aspects, molecular virology, and diagnostic approaches of CHIKV infection.
Keywords: Anti-chikungunya plants, antiviral therapy, chikungunya virus, clinical aspects, Flavonoids, molecular virology, natural antivirals, pathogenesis
How to cite this article:
Kumar S, Garg C, Kaushik S, Buttar HS, Garg M. Demystifying therapeutic potential of medicinal plants against chikungunya virus. Indian J Pharmacol 2021;53:403-11 |
How to cite this URL:
Kumar S, Garg C, Kaushik S, Buttar HS, Garg M. Demystifying therapeutic potential of medicinal plants against chikungunya virus. Indian J Pharmacol [serial online] 2021 [cited 2023 May 30];53:403-11. Available from: https://www.ijp-online.com/text.asp?2021/53/5/403/331087 |
| » Introduction | |  |
Infectious diseases have also evolved during human species evolution. The new infections emergence and recurrence of existing ones are posing a threat to society. Among these, viral infections account for several casualties each year and constitute serious health issues worldwide because of the nonspecificity of antiviral therapies.[1],[2]
Chikungunya virus (CHIKV) that belongs to the Togaviridae family is a re-emerging mosquito-borne infection, transmitted by the bite of infected female Aedes mosquitoes.[1] It was firstly identified in the Makonde plateau (Tanzania) in 1952 and named after the word “kungunyala,” meaning “that which bends up,” denoting the bent pose of CHIKV infected person due to severe joint pain. From the time of the first 1952 report, it caused infrequent outbreaks mostly in Africa and Southeast Asia until its global re-emergence which started in 2004 from Kenya and spreads through neighbor islands to several Indian Ocean islands and finally to India.[3],[4] During these epidemics, it has infected more than 6 million people.[4],[5] Further, it has approximately infected one million people in the American continent by 2014.[1],[6] All these outbreaks related to CHIKV take place in Africa, Southeast Asia, India, and recently in the American continent have established chikungunya a major global health problem that continues to expand at an alarming rate.[7] The disease is rarely fatal, but persistent severe polyarthritis affects the quality of life and reduces the workability of patients.[8] Unfortunately, treatment is only confined to relieving symptoms by analgesics, antipyretics, corticosteroids, and anti-inflammatory drugs, but does not cure a viral infection. Furthermore, there is no approved CHIKV vaccine or antiviral therapy for treatment and prophylaxis yet.[6] Thus it is prudent to find novel anti-chikungunya drugs that may be used either as therapies or as preventative measures to combat the deadly epidemics.
Almost all civilizations have used and continue to use medicine from natural sources. Among all-natural sources, medicinal plants have been the most widely used source of safe and effective medicine.[9] The chemical constituents of medicinal plants have served as a rich source of new therapeutics during the process of drug development and discovery. Almost 50% of currently available therapeutics is obtained from natural sources, using either natural products or natural products synthetic analogs. Medicinal plants have been used to control infectious diseases since time immemorial. During the last few years, several studies have reported some natural products[10],[11] and approved drugs[12] having in vitro anti-chikungunya activity. Studies have also revealed the antiviral potential of medicinal plants against the CHIKV.[1],[13]
The research articles, published from 2011 to 2021, are selected from Google Scholar, MEDLINE, and PubMed by using relevant keywords including the anti-CHIKV potential of plants, the antiviral activity of plants against Chikungunya, plant and natural products used in CHIKV infection, virology of CHIKV. The research articles primarily focusing on the anti-CHIKV activity of plant extracts, pure compounds of natural origin, and their synthetic analog are included in the study.
| » Pathogenesis | | |
Among its symptoms, severe joint pain may continue for several weeks to years in 10% of the infected population.[14] Based on the duration of symptoms, the disease can be divided into the acute, postacute, and chronic phases. The acute phase of the disease includes the first 3 weeks of infection which consists of incubation periods of 4–7 days, after which symptoms such as fever, arthralgia, and maculopapular rash last for 5–10 days.[15],[16] The postacute phase begins from the 4th week of infection and lasts up to the end of the 3rd month. In this phase severity of the acute phase, complications increased. When symptoms persist after the 3rd month, the disease enters its chronic phase which results in persistent severe polyarthritis almost in 60% of infected patients.[1] Dengue and Zika viruses show similar symptoms of CHIKV like fever, arthralgia, maculopapular rashes, and usually co-circulate in the epidemic regions of CHIKV, thereby they can easily co-infect the patients.[17],[18],[19] Therefore, specific diagnostic tests for early-phase infection diagnosis are important. Based upon specimen collection time, a diagnostic method is selected from the various available virological, genetic, and serological methods.[17]
| » Virology | | |
CHIKV is spherical, positive-sense single-stranded RNA encapsidated within icosahedral capsid which is enveloped with lipid-bilayer membrane. The icosahedral capsid of a virus is approximately 65 nm diameter and the genome is around 12 kb long which has two open reading frames one on each end of RNA. The 5' end of RNA encodes four nonstructural proteins (nsP1 to nsP4) and 3' end encodes five structural proteins (1 capsid protein, 2 glycoproteins E1 and E2, 2 cleavage products E3 and 6K).[20],[21] The different genotypes of the virus have distinct antigenic characteristics and named according to their geographical sources.[22]
| » Plant Extracts Targeting chikungunya virus Infection | | |
Ipomoea aquatica
This is a semi-aquatic tropical plant, commonly called “Water Morning Glory” grown extensively as a leaf vegetable throughout the world; chemically consists of alkaloids, carbohydrates, flavonoids (nicotiflorin and ramnazin-3-O-rutinoside), and phenolic compounds.[23] Chan et al.[13] evaluated the anti-CHIKV activity of the aerial parts extracted with six solvents of different polarities [Table 1]. Among different extracts, only ethyl acetate extract strongly inhibited the cytopathic effect of CHIKV in Vero cell lines exhibiting 82% cell viability (at 320 μg/ml) by the neutral red uptake assay. Chloroquine was used as a positive control. Further quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of the above extract showed a reduction in viral load by 65% (at 320 μg/ml) as compared to virus control. | Table 1: Cytotoxicity and anti-chikungunya activity of plant extracts in Vero cells by cytopathic effect inhibition assay[13]
Click here to view |
Persicaria odorata
Persicaria odorata commonly called “Vietnamese coriander” in Malaysia, consists of steroids, terpenoids, flavonoids, tannins and phenolic compounds, carbohydrates and exhibits anti-infective activities.[24] Chan et al.[13] examined the anti-CHIKV activity of six different solvent extracts of the aerial parts [Table 1]. Ethanolic extract strongly inhibited the cytopathic effect of CHIKV with cell viability of more than 70% while metabolic extract showed moderate inhibition exhibiting cell viability <50%. Chloroquine was used as the positive control and the cell viability was measured by the neutral red uptake assay. In quantitative RT-PCR, ethanol extract reduced the Chikungunya viral load by 90% (at 160 μg/ml) in comparison to virus control. Hence, ethanol-soluble extractives could be a good source of anti-CHIKV drugs.
Rhapis excelsa
Methanolic extract of leaves of Rhapis excelsa, commonly known as “lady palm” contains 4 flavonoids: Apigenin-8-C-glucoside (vitexin), Apigenin-6, 8-Di-C-βglucopyranoside (vicenin-2), Luteolin-6-C-glucoside (iso-orientin), and Luteolin-8-C-glucoside (orientin).[25] In a study performed by Chan et al.,[13] leaves extracted with solvents of a wide polarity range and screened for their anti-CHIKV activity. Out of six extracts, chloroform extract (30 μg/ml) exhibited the strongest inhibition of the cytopathic effect of the CHIKV without significant cytotoxicity. The strong anti-chikungunya activity of the extract is further confirmed by quantitative RT-PCR analysis in which extract reduced the viral load by 98% in comparison to virus control. These results suggest that this extract might have direct virucidal effects on CHIKV.
Tradescantia spathacea
This is a tropical plant, commonly known as “oyster plant” used as laxatives, a blood thinner, antibiotic and anti-malaria; consist of alkaloids, flavonoids, glycosides, saponin, and tannins.[26] Chan et al.[13] investigated in vitro antiviral activity of Tradescantia spathacea leaves extracts as a powerful anti-chikungunya plant. The ethanol and methanol extracts, at concentration 512 μg/ml, exhibited strong inhibitory activity against the CHIKV with cell viabilities 93% and 91%, respectively, while chloroform extract showed 89% cell viability at concentration 80 μg/ml. The results of quantitative RT-PCR revealed that the percentage reduction in viral load of ethanol, methanol, and chloroform extracts were 53%, 46%, and 84%, respectively. The above results suggest that active extracts of this plant might inhibit the virus to infect other cells and also exhibit the direct virucidal effect.
Vernonia amygdalina
The leaves of Vernonia amygdalina, commonly called “Bitter leaf” contain alkaloids, glycosides, saponins, quercetin, epicatechin, steroids, coumarins, polyphenolic compounds, mucilage, pectin, lipids, and terpenoids.[27] Chan et al.[13] investigated the antiviral activity of V. amygdalina leaves extract against CHIKV in vitro [Table 1]. Out of six extracts only ethyl acetate, ethanol, and methanol extract exhibited strong cytopathic effect inhibitory activity with cell viability of more than 70%. The acetate extract had the lowest cytotoxicity among all six extracts. In quantitative RT-PCR analysis, the percentage reduction in viral load of ethyl acetate, ethanol, and methanol extracts were 95, 83, and 82 at a concentration of 80, 160, and 320 μg/ml, respectively. Treatment with ethyl acetate extract resulted in the highest reduction in virus load using the lowest concentration.
Andrographis paniculata
It is a traditional medicinal plant, commonly known as King of bitters or Kalmegh; used to treat infections; mainly contain diterpenoid: Andrographolide. Sharma et al.[28] evaluated the anti-CHIKV potential of silver nanoparticles of aqueous leaf extract by calculating the cell viability of virus-infected Vero cells after treatment with extract nanoparticles. In this study, the viability of untreated infected Vero cells which was 25%, increased to about 81% when treated with a maximum nontoxic dose (MNTD) 31.25 μg/ml of silver nanoparticles synthesized from aqueous leaf extract of the plant. The results indicate that it has significant anti-CHIKV potential [Table 2]. | Table 2: Antichikungunya activity of plant extracts in Vero cells by cytopathic effect inhibition assay
Click here to view |
Phyllanthus niruri
Phyllanthus niruri, commonly called “stone breaker,” is used as antiulcer, hypolipidemic, antiviral and antioxidant in Ayurveda formulations. Sharma et al.[28] prepared the silver nanoparticles of aqueous leaf extract of P. niruri which showed MNTD 125 μg/ml in Vero cells determined by using MTT assay. The FTIR spectra indicate that these nanoparticles consist of flavonoids, polyols, terpenoids, and polyphenols. In the present investigation, the cell viability of untreated infected Vero cells which was 25%, increased to about 30% only when treated with MNTD. The results indicate that it does not have significant anti-CHIKV potential [Table 2].
Tinospora cordifolia
Tinospora cordifolia commonly known as “Guduchi” is renowned in Ayurveda literature for its uses in the therapy of different diseases and is a source of bioactive components like alkaloids, terpenoids, glycosides, and steroids. However, FTIR spectra also indicate the presence of flavonoids, polyols, and polyphenols.[28],[32] In a study performed by Sharma et al.,[28] silver nanoparticles prepared by treatment of 1 mM aqueous solution of AgNO3 with aqueous extract of this plant stem showed antiviral activity against CHIKV in Vero cell lines. The cell viability of untreated infected Vero cells which was 25%, increased to about 75% when treated with MNTD (250 μg/ml) of these nanoparticles and exhibited about 49% of inhibition activity against the virus. The results indicate that it has significant anti-CHIKV potential [Table 2]. However, in another study, when aqueous extract of stem evaluated for anti-CHIKV activity by Plaque reduction assay, Helicase assay and Protease assay, it did not show antiviral activity in any assay.[33]
Oroxylum indicum
It is a threatened medicinal plant, commonly called the Indian trumpet tree, extensively cultivated in Southeast Asia, India, and China; chemically contains several flavonoids.[34] Mohamat et al.[29] evaluated the anti-CHIK potential of leaves extracted with methanol and water [Table 2]. In cytotoxicity assay, the MNTD (cell viability similar to negative control) of both methanol and aqueous extract was 625 μg/ml. The value of CC50 (cell viability 50%) for methanol and aqueous extracts in Vero cell lines was 1875 and 7700 μg/ml, respectively. Although both extracts, aqueous and methanol, had a poor anti-CHIKV effect comparatively aqueous extract demonstrated higher antiviral potential and reduced viral titer 10% when assessed with a concentration of 150 μg/ml. Although both extracts did not show a direct virucidal effect significantly the aqueous extract affected virus entry as suggested by the Plaque reduction assay.
Cynodon dactylon
It is commonly called Bermuda Grass, family Poaceae. It consists of glycosides, phytosterols, polysaccharides, flavonoids, terpenes, and alkaloids as bioactive constituents. In a study performed by Murali et al.,[30] fractions of ethanolic extract of fresh plant material were separated using chromatographic techniques and then evaluated for anti-CHIV activity in Vero cells [Table 2]. The flavonoid-rich fraction exhibited potent anti-chikungunya activity (98% inhibition) at the concentration of 50 μg/ml and it was found safe to use even up to 250 μg/ml concentration as determined by cytotoxicity studies. The active compounds of this fraction were further identified by Reverse Phase-high-performance liquid chromatography and gas chromatography-mass spectrometry. The flavonoids luteolin and apigenin have shown promising results as anti-CHIKV agents.
Picrorhiza kurroa
This is commonly called Katuki; consists of kutkin (kutkosides and iridoid glycosides) and apocynin (catechol) as major bioactive constituents. The aqueous extract (10 μg/ml) of rhizomes of this plant inhibited CHIKV more than 80% without causing cytotoxicity in plaque reduction assay suggesting extract a viral attachment inhibitor. The plant extract also inhibited helicase enzyme activity in helicase assay suggesting it as a viral replication inhibitor. Further, it was subjected to a virus replication inhibition assay in which it showed 38.3% and 67% viral replication inhibition at concentrations 100 μg/ml and 200 μg/ml respectively [Table 3].[33] | Table 3: Antichikungunya activity of plant aqueous extracts in Vero cells[33]
Click here to view |
Ocimum tenuiflorum
This is a holy plant, commonly known as “Shyama Tulsi” consist of mainly phenyl derivative compounds, methyl eugenol, and other terpenoids.[35] Raghavendhar et al.[33] demonstrated the complete antiviral ability of aqueous extract of the whole plant and recommended it for further investigations like in vivo studies. In this study, extract exhibited complete anti-CHIKV ability by inhibiting virus in plaque reduction (more than 80% inhibition), helicase, and protease assay. Results demonstrated the ability of the extract to inhibit CHIKV attachment, its entry and replication. In a replication inhibition assay, the Ocimum tenuiflorum extract exhibited a positive effect against CHIKV by 28.3%, 53.3%, 85%, and 100% at experimental concentrations of 25, 50, 100, and 200 μg/ml, respectively [Table 3].
Terminalia chebula
It is commonly known as Haritaki; consists of tannins, flavonoids (flavonol glycosides), terpenoids, saponin, sterols.[36] Raghavendhar et al.[33] demonstrated the complete antiviral ability of aqueous extract of the fruit. This extract exhibited complete antiviral potential against CHIKV by inhibiting virus in plaque reduction (more than 80% inhibition), helicase, and protease assay. Results demonstrated the ability of the extract to inhibit CHIKV attachment, its entry, and replication. The extract demonstrated dose-dependent inhibition in replication inhibition assay and showed 23%, 51.6%, 83.3%, and 100% inhibition of CHIKV at concentration 25, 50, 100, and 200 μg/ml [Table 3].
Zingiber officinale
Rhizomes consist of bioactive constituents like terpenoids, steroids, gingerols, gingerones, shogaols, tetra, and hexa-hydrocurcumin; commonly called Saunth.[37] Raghavendhar et al.[33] evaluated the anti-CHIKV potential of aqueous extract of rhizomes of this plant by plaque reduction, helicase, and protease assay. The extract (10 μg/ml) exhibited anti-CHIKV activity by inhibited RNA helicase enzyme only in helicase assay suggesting it as a viral replication inhibitor but it did not inhibit virus in plaque reduction assay and protease assay [Table 3]. In another study, the aqueous extracts of fresh dried rhizomes exhibited anti-chikungunya potential by reducing the cytopathic effect of CHIKV in Vero cell lines, and increased the survival of cells by 51.05% and 35.10%, when pretreated with MNTD 62.5 μg/ml and half of MNTD, respectively. Likewise, the survival of Vero cells increased by 52.90% and 49.02% when co-treated with MNTD and half of MNTD, respectively.[38]
Commiphora wightii
The plant gum resin is commonly used for arthritis, high blood cholesterol, atherosclerosis, and skin disease; mainly consists of terpenoids, steroids, guggulstetrols, flavonoids, Guggulsterones E and Z.[39] Raghavendhar et al.[33] evaluated the anti-CHIKV potential of the resin obtained from this plant by plaque reduction, helicase and protease assay. The resin exhibited viral plaque inhibition at concentration 10 μg/ml in plaque reduction assay suggesting resin as a viral attachment inhibitor. It also inhibited virus replication 31.6% at concentration 200 μg/ml in virus replication inhibition assay [Table 3].
Cedrus deodara
It is commonly called Devdaru; bark contains bioactive principles such as cedeodarin, α-pinene, β-pinene, myrcene, cedrin. The aqueous extract of bark of this plant exhibited viral plaque inhibition at concentration 10 μg/ml in plaque reduction assay suggesting it as a viral attachment inhibitor. However, it also suggested as a CHIKV replication inhibitor in virus replication inhibition assay in which it inhibited virus replication 36.6% at concentration 200 μg/ml [Table 3].[33]
Alpinia officinarum
The aqueous, ethanolic and aqueous-ethanolic extracts of rhizomes of this plant showed antiviral activity against Asian CHIKV in Vero cell lines at concentrations of 72.5 μg/ml, 125 μg/ml, and 72.5 μg/ml respectively. The selectivity indices of the extracts were 3.44, 2, and 6. These extracts did not inhibit the growth of the ECSA lineage of CHIKV in the same experimental conditions.[40]
Melia azedarach
In Vero cell lines, an ethanolic extract of this plant's leaves showed anti-CHIKV efficacy against Asian and ECSA strains at concentrations of 31.25 g/ml and 125 g/ml, respectively. The selectivity indices of the extract for Asian and African strains were 8 and 2, respectively.[40]
Azadirachta indica
The aqueous and aqueous ethanolic extracts of leaves of this plant inhibited the growth of Asian CHIKV in Vero cell lines at concentrations of 62.5 μg/ml and 32.25 μg/ml. The selectivity indices of the extracts were 1 and 2. These extracts did not inhibit the growth of the ECSA lineage of CHIKV in the same experimental conditions.[34] In another study, the aqueous extract of bark of the plant did not show anti-CHIKV activity in the Plaque reduction assay, Helicase assay, and Protease assay.[33]
Psidium guajava
The aqueous extracts of leaves and their green synthesized silver nanoparticles reduced the cytopathic effect of CHIKV in Vero cell lines and increased the survival of cells by 60% and 40% in comparison to the virus control, respectively. This indicates the antiviral potential of this plant against CHIKV. In cytotoxicity assay, both extract and nanoparticles showed MNTD 15 μg/ml in Vero cells determined by using MTT assay. Docking studies found that the phytochemicals; longifollen and quercetin interact with a replication essential cysteine protease (nsP2) of CHIKV which may be the mechanism of antiviral activity.[31]
| » Phytochemicals Targeting chikungunya virus Infection | | |
Epigallocatechin gallate
Among catechins present in green tea extract, Epigallocatechin gallate (EGCG) is the most important, concerning antiviral properties against many viruses including HIV, influenza, and hepatitis C. EGCG was reported to reduce the infection rate of CHIKV 40% at a concentration of 10 μg/ml which clearly shows significant inhibition. The compound inhibited the entry of CHIKV pseudo-particles into the target cell.[41]
Curcumin
It is a bioactive constituent of turmeric rhizomes which are used as a spice in food and herbal supplement. In a study performed by Mounce et al.[42] Curcumin, a component of turmeric rhizomes, exhibited anti-chikungunya activity by inhibiting viral replication and cell binding of the virus in a dose-dependent manner. In further investigation, Curcumin directly reduced the infectivity of the virus in a time and dose-dependent manner.
Harringtonine and its analog homoharringtonine
Cephalotaxus harringtonia mainly consists of alkaloids and terpenoids. Harringtonine, an alkaloid from this plant and its analog homoharringtonine exhibited in vitro anti-CHIKV activity in BHK21 cells. The results of time-of-addition studies suggested that Harringtonine inhibited viral replication after entry into the cell but did not have any effect on the binding and entry of the virus into a cell.[43]
Silymarin
It is an extract from the seeds of Silybum marianum commonly called Milk Thistle; consists of several flavonolignans and a few flavonoids. Lani et al.[10] investigated the silymarin, quercetin, and kaempferol for anti-CHIKV activity using a CHIKV replicon cell line. Silymarin at 100 μg/ml significantly inhibited the CHIKV mediated cytotoxicity in the CPE inhibition assay and resulted in about 70% inhibition of CHIKV infection. In the postadsorption assay, silymarin at this concentration inhibited CHIKV replication about 99%, in dose-dependent mode. Both quercetin and kaempferol at 200 μg/ml exhibited only 25% CPE inhibition. These findings showed that silymarin had potent antiviral action against CHIKV in vitro conditions, reducing viral replication in the virus's postentry stage in a dose-dependent manner.
Andrographolides
Andrographolide, a major bioactive phytochemical, is extracted from the leaves of Andrographis paniculata which is traditionally used to treat infections. Based on this, Wintachai et al.[44] evaluated the antiviral potential of andrographolide against ECSA genotype of CHIKV in human liver cell lines HepG2. Andrographolide showed potent anti-chikungunya activity in plaque assay, with 50% inhibitory concentration 77 μM without cytotoxicity. In this study, andrographolide reduced viral infection in a dose-dependent manner, with 80% inhibition at 100 μM as determined by flow cytometry and confirmed by confocal microscopy. Time of addition and RNA transfection studies suggested that it inhibited viral genome replication at the postentry step.
Nobiletin
The active ingredients of citrus fruits are well known for their wide range of pharmacological activities. The peels of Citrus reticulate consist of flavonoid Nobiletin as a bioactive ingredient in large quantity. Lin et al.[45] evaluated the anti-CHIKV potential of four natural flavonoids: Nobiletin, phlorizin, resveratrol, and oxyreveratrol in Vero E6 cells by neutral red uptake assay. Among these flavonoids, Nobiletin and resveratrol exhibited significant antiviral activity against the CHIKV, but oxyreveratrol and phlorizin did not. The data of MTT assay and lactate dehydrogenase assay revealed that nobiletin (at 250, 200, 150, and 100 μM) reduced viral cytotoxicity, viral yield, and maintained cell proliferation. Besides, it reduced the CPE of the virus within the host cell after 48 h of infection.
Flavaglines
Flavaglines are class of natural compounds derived from plants of genus Aglaia, family Meliaceae; have potent anti-cancer and neuroprotective potential. Wintachai et al.[46] investigated the anti-chikungunya activity of three synthetic flavaglines in the human embryonic kidney cell line Hek293T/17. Three compounds show the inhibition of CHIKV entry and production when cells were treated for only 15 min before infection but not when treated after infection. One compound exhibited moderate antiviral activity by inhibiting CHIKV replication.
Phytochemicals of Tectona grandis Lin
In a study, phytochemicals from the leaves of Tectona grandis were isolated and evaluated for the anti-CHIKV potential.[47] Three compounds were isolated: 2-(butoxycarbonyl) benzoic acid, 3, 7, 11, 15-tetramethyl-1-hexadecanol, and benzene-1-carboxylic acid-2-hexadeconate. These compounds were evaluated for antiviral potential against Asian and African strains of CHIKV by MTT assay using ribavirin as a positive control. These compounds showed selectivity indices 136, 156, 116, and 11.88, 2.11, 4.66 to Asian and African strains, respectively.
Baicalein, fisetin, and quercetagetin
Lani et al.[48] evaluated the antiviral activity of these flavonoids against the ECSA genotype of the CHIKV in Vero cells using various antiviral assays. Baicalein, fisetin, and quercetagetin exhibited strong antiviral activity, with IC50 values of 1.891 mg/ml, 8.444 mg/ml, and 13.85 mg/ml, respectively, and without significant cytotoxicity. The results of different antiviral assays revealed that baicalein and quercetagetin mostly reduced virus attachment to Vero cells in a dose-dependent manner, indicating extracellular anti-CHIKV action [Table 4]. The Western blotting data suggested that fisetin inhibited the translation of nonstructural proteins which reduced the production of replicas units. The western blotting analysis also provided pieces of evidence of intracellular anti-CHIKV activity of these flavonoids. | Table 4: Antichikungunya activity of baicalein, fisetin, and quercetagetin in Vero cells[48]
Click here to view |
| » Polyherbal Formulation | | |
Nilavembu Kudineer
Nilavembu Kudineer is a polyherbal formula with A. paniculata as its main herb. The other component plants are Cyperus rotandus, Mollugo cerviana, Piper nigrum, Santalum album, Trichosanthes cucumerina, Vetiveria zizanioides and Zingeber officinale. Ethanolic extract of Nilavembu Kudineer showed a protective effect against CHIKV infection in Vero cells.[49]
| » Discussion | | |
The newly emerging arboviral diseases like Dengue, CHIK, Zika, have raised a serious health concern over the years.[40],[50] Cross countries travel and climate change increases the chances to further import these infections in new areas thus need necessary attention and research to avoid serious human threats.[21] The scientific community all over the world is trying to develop a solution through different mechanisms. In these efforts, many medicinal plant extracts and their phytochemicals have demonstrated potential efficacy through in-vitro models depicting inhibition of CHIKV via different antiviral modes of action.[13],[28],[29],[30],[33],[31],[51]
Despite numerous efforts made to examine the antiviral activity, still, efficacy and toxicity assessment demand further investigations and evidence. As exhibited in [Table 1], [Table 2], [Table 3] and [Figure 1], efficacy and toxicity fluctuate significantly relying upon the solvent extracts and assay methods. Some solvent extracts like alcoholic and aqueous extracts (mostly containing flavonoids) found more efficacious in comparison to other solvent extracts almost in all the studies [Figure 1]. Only two chloroform and two ethyl acetate extracts showed significant anti-CHIKV activity. The efficacy and toxicity are estimated based on % viral inhibition and selectivity index (SI) which in turn are significant for choosing extracts or phytochemicals to analyze in-vivo. So far, only a SI value ≥10 is typically considered for animal studies and a characterized cut-off value yet to be decided.[6] Future research on a more thorough validation of evaluation parameters for determining efficacy and toxicity of extracts or phytochemicals in in-vitro studies (e.g. multiple assay methods) might help in the success of them in-vivo assays and accelerate the drug development for CHIKV infection. | Figure 1: Comparison of the anti-chikungunya activity of extracts of different solvent
Click here to view |
Although extracts are a rich source of chemical diversity, as all the flavonoid-rich extracts[28],[30] and even some isolated flavonoids like silymarin,[10] nobiletin,[45] baicalein, fisetin, and quercetagetin[48] exhibited potent anti-CHIKV activity, it is believed that the presence of flavonoids in extracts would have contributed significantly to anti-CHIKV activity. This belief is further supported by the fact that flavonoids show antiviral against other arboviruses (eg., CHIKV, Dengue, and Zika virus).[10],[45],[48],[52] Therefore, screening of flavonoids containing plants would be more fruitful for the discovery of new leads for anti-CHIKV drug development. Further, it will also be prudent to screen many other antiviral phytochemicals such as silymarin, nobiletin, Curcumin, and resveratrol which have already been approved for various viral sicknesses.[10],[42],[45]
Aside from showing antiviral action against CHIKV, silymarin, resveratrol, baicalein, fisetin, Curcumin, and ECGC additionally show antiviral action against Dengue or Zika virus or both in vitro.[42],[52],[53],[54],[55],[56] Hence, further research on these phytochemicals would be ideal as CHIKV usually co-circulates and simultaneously co-infects with these arboviruses (e.g. Dengue or Zika virus) which are also transmitted by the same vector (Aedes species).[18],[19],[57]
| » Conclusion | | |
Scientific studies have shown the therapeutic effectiveness of medicinal plants and few phytochemicals with sufficient future potential against the CHIKV. Further studies for their therapeutic efficacy in animal models, safety profiles, and mechanisms of action at the molecular level may lead to finding out a suitable remedy.
Acknowledgment
The authors would like to acknowledge University Grants Commission for financial grants sanctioned to the department under SAP at DRS Level-II.
Financial support and sponsorship
As mentioned above.
Conflicts of interest
There are no conflicts of interest.
| » References | | |
| 1. | da Silva-Júnior EF, Leoncini GO, Rodrigues ÉE, Aquino TM, Araújo-Júnior JX. The medicinal chemistry of Chikungunya virus. Bioorg Med Chem 2017;25:4219-44.  |
| 2. | Ledoux A, Cao M, Jansen O, Mamede L, Campos PE, Payet B, et al. Antiplasmodial, anti-Chikungunya virus and antioxidant activities of 64 endemic plants from the Mascarene Islands. Int J Antimicrob Agents 2018;52:622-8. |
| 3. | Shanmugaraj B, Malla A, Ramalingam S. Epidemiology, clinical features and transmission of re-emerging arboviral infection Chikungunya. Asian Pac J Trop Biomed 2019;9:135-9. [Full text] |
| 4. | Sengupta S, Mukherjee S, Haldar SK, Bhattacharya N, Tripathi A. Re-emergence of Chikungunya virus infection in Eastern India. Braz J Microbiol 2020;51:177-82. |
| 5. | Deeba F, Haider MS, Ahmed A, Tazeen A, Faizan MI, Salam N, et al. Global transmission and evolutionary dynamics of the Chikungunya virus. Epidemiol Infect 2020;148:e63. |
| 6. | Subudhi BB, Chattopadhyay S, Mishra P, Kumar A. Current strategies for inhibition of chikungunya infection. Viruses 2018;10:E235. |
| 7. | Tan Y, Pickett BE, Shrivastava S, Gresh L, Balmaseda A, Amedeo P, et al. Differing epidemiological dynamics of Chikungunya virus in the Americas during the 2014-2015 epidemic. PLoS Negl Trop Dis 2018;12:e0006670. |
| 8. | Vairo F, Haider N, Kock R, Ntoumi F, Ippolito G, Zumla A. Chikungunya: Epidemiology, pathogenesis, clinical features, management, and prevention. Infect Dis Clin North Am 2019;33:1003-25. |
| 9. | Mohan S, Elhassan Taha MM, Makeen HA, Alhazmi HA, Al Bratty M, Sultana S, et al. Bioactive natural antivirals: An updated review of the available plants and isolated molecules. Molecules 2020;25:E4878. |
| 10. | Lani R, Hassandarvish P, Chiam CW, Moghaddam E, Chu JJ, Rausalu K, et al. Antiviral activity of silymarin against Chikungunya virus. Sci Rep 2015;5:11421. |
| 11. | Martins DO, Santos IA, de Oliveira DM, Grosche VR, Jardim AC. Antivirals against Chikungunya virus: Is the solution in nature? Viruses 2020;12:E272. |
| 12. | Tripathi PK, Soni A, Singh Yadav SP, Kumar A, Gaurav N, Raghavendhar S, et al. Evaluation of novobiocin and telmisartan for anti-CHIKV activity. Virology 2020;548:250-60. |
| 13. | Chan YS, Khoo KS, Sit NW. Investigation of twenty selected medicinal plants from Malaysia for anti-Chikungunya virus activity. Int Microbiol 2016;19:175-82. |
| 14. | Schilte C, Staikowsky F, Couderc T, Madec Y, Carpentier F, Kassab S, et al. Chikungunya virus-associated long-term arthralgia: A 36-month prospective longitudinal study. PLoS Negl Trop Dis 2013;7:e2137. |
| 15. | Pérez-Pérez MJ, Delang L, Ng LF, Priego EM. Chikungunya virus drug discovery: Still a long way to go? Expert Opin Drug Discov 2019;14:855-66. |
| 16. | Bourjot M, Delang L, Nguyen VH, Neyts J, Guéritte F, Leyssen P, et al. Prostratin and 12-O-tetradecanoylphorbol 13-acetate are potent and selective inhibitors of Chikungunya virus replication. J Nat Prod 2012;75:2183-7. |
| 17. | An W, Ge N, Cao Y, Sun J, Jin X. Recent progress on Chikungunya virus research. Virol Sin 2017;32:441-53. |
| 18. | Hisamuddin M, Tazeen A, Abdullah M, Islamuddin M, Parveen N, Islam A, et al. Co-circulation of Chikungunya and dengue viruses in dengue endemic region of New Delhi, India during 2016. Epidemiol Infect 2018;146:1642-53. |
| 19. | Morgan J, Strode C, Salcedo-Sora JE. Climatic and socio-economic factors supporting the co-circulation of dengue, Zika and Chikungunya in three different ecosystems in Colombia. PLoS Negl Trop Dis 2021;15:e0009259. |
| 20. | Kendall C, Khalid H, Müller M, Banda DH, Kohl A, Merits A, et al. Structural and phenotypic analysis of Chikungunya virus RNA replication elements. Nucleic Acids Res 2019;47:9296-312. |
| 21. | Hucke FI, Bugert JJ. Current and promising antivirals against Chikungunya virus. Front Public Health 2020;8:618624. |
| 22. | Wahid B, Ali A, Rafique S, Idrees M. Global expansion of Chikungunya virus: Mapping the 64-year history. Int J Infect Dis 2017;58:69-76. |
| 23. | Hefny Gad M, Tuenter E, El-Sawi N, Younes S, El-Ghadban EM, Demeyer K, et al. Identification of some bioactive metabolites in a fractionated methanol extract from ipomoea aquatica (Aerial Parts) through TLC, HPLC, UPLC-ESI-QTOF-MS and LC-SPE-NMR fingerprints analyses. Phytochem Anal 2018;29:5-15. |
| 24. | Řebíčková K, Bajer T, Šilha D, Houdková M, Ventura K, Bajerová P. Chemical composition and determination of the antibacterial activity of essential oils in liquid and vapor phases extracted from two different southeast Asian herbs- Houttuynia cordata (Saururaceae) and Persicaria odorata (Polygonaceae). Molecules 2020;25:2432. |
| 25. | Hassanein HD, Elsayed WM, Abreu AC, Simões M, Abdelmohsen MM. Polyphenolic constituents and antimicrobial activity of Rhapis excels ( Arecaceae, Coryphoideae). RJPBCS 2015;6:1714-22. |
| 26. | Kadam PM, Kakde NP. Phytochemical study of Tradescantia spathacea. Int Res J Biological Sci 2017;6:48-51. |
| 27. | Erukainure OL, Chukwuma CI, Sanni O, Matsabisa MG, Islam MS. Histochemistry, phenolic content, antioxidant, and anti-diabetic activities of Vernonia amygdalina leaf extract. J Food Biochem 2019;43:e12737. |
| 28. | Sharma V, Kaushik S, Pandit P, Dhull D, Yadav JP, Kaushik S. Green synthesis of silver nanoparticles from medicinal plants and evaluation of their antiviral potential against Chikungunya virus. Appl Microbiol Biotechnol 2019;103:881-91. |
| 29. | Mohamat SA, Shueb RH, Che Mat NF. Anti-viral activities of Oroxylum indicum extracts on Chikungunya virus infection. Indian J Microbiol 2018;58:68-75. |
| 30. | Murali KS, Sivasubramanian S, Vincent S, Murugan SB, Giridaran B, Dinesh S, et al. Anti-chikungunya activity of luteolin and apigenin rich fraction from Cynodon dactylon. Asian Pac J Trop Med 2015;8:352-8. |
| 31. | Sharma Y, Kawatra A, Sharma V, Dhull D, Kaushik S, Yadav JP, et al. In-vitro and in-silico evaluation of the anti-chikungunya potential of Psidium guajava leaf extract and their synthesized silver nanoparticles. Virusdisease 2021;32:1-6. |
| 32. | Sharma P, Dwivedee BP, Bisht D, Dash AK, Kumar D. The chemical constituents and diverse pharmacological importance of Tinospora cordifolia. Heliyon 2019;5:e02437. |
| 33. | Raghavendhar S, Tripati PK, Ray P, Patel AK. Evaluation of medicinal herbs for Anti-CHIKV activity. Virology 2019;533:45-9. |
| 34. | Peng Q, Shang X, Zhu C, Qin S, Zhou Y, Liao Q, et al. Qualitative and quantitative evaluation of Oroxylum indicum (L.) Kurz by HPLC and LC-qTOF-MS/MS. Biomed Chromatogr 2019;33:e4657. |
| 35. | Maurya S, Chandra M, Yadav RK, Narnoliya LK, Sangwan RS, Bansal S, et al. Interspecies comparative features of trichomes in Ocimum reveal insights for biosynthesis of specialized essential oil metabolites. Protoplasma 2019;256:893-907. |
| 36. | Promila P, Madan VK. Therapeutic and phytochemical profiling of Terminalia chebula Retz. (Harad): A review. J Med Plants Stud 2018;6:25-31. |
| 37. | Sharma K, Sahai M. Chemical constituents of Zingiber officinale rhizome. J Med Plants Stud 2018;6:146-9. |
| 38. | Kaushik S, Jangra G, Kundu V, Yadav JP, Kaushik S. Anti-viral activity of Zingiber officinale (Ginger) ingredients against the Chikungunya virus. Virusdisease 2020;31:1-7. |
| 39. | Jaiswal S, Bara JK, Soni R, Saksena P. Medical uses of Commiphora wightii. IOSR J Nurs Health Sci 2016;5:76-81. |
| 40. | Sangeetha K, Rajarajan S. In-vitro antiviral activity of Indian medicinal plants to Asian and East Central South African lineage of Chikungunya virus. IJPSR 2015;6:692-7. |
| 41. | Weber C, Sliva K, von Rhein C, Kümmerer BM, Schnierle BS. The green tea catechin, epigallocatechin gallate inhibits Chikungunya virus infection. Antiviral Res 2015;113:1-3. |
| 42. | Mounce BC, Cesaro T, Carrau L, Vallet T, Vignuzzi M. Curcumin inhibits Zika and Chikungunya virus infection by inhibiting cell binding. Antivir Res 2017;142:148-57. |
| 43. | Kaur P, Thiruchelvan M, Lee RC, Chen H, Chen KC, Ng ML, et al. Inhibition of Chikungunya virus replication by harringtonine, a novel antiviral that suppresses viral protein expression. Antimicrob Agents Chemother 2013;57:155-67. |
| 44. | Wintachai P, Kaur P, Lee RC, Ramphan S, Kuadkitkan A, Wikan N, et al. Activity of andrographolide against Chikungunya virus infection. Sci Rep 2015;5:14179. |
| 45. | Lin SC, Chen MC, Li S, Lin CC, Wang TT. Antiviral activity of nobiletin against Chikungunya virus in vitro. Antivir Ther 2017;22:689-97. |
| 46. | Wintachai P, Thuaud F, Basmadjian C, Roytrakul S, Ubol S, Désaubry L, et al. Assessment of flavaglines as potential Chikungunya virus entry inhibitors. Microbiol Immunol 2015;59:129-41. |
| 47. | Sangeetha K, Purushothaman I, Rajarajan S. Spectral characterisation, antiviral activities, in silico ADMET and molecular docking of the compounds isolated from Tectona grandis to Chikungunya virus. Biomed Pharmacother 2017;87:302-10. |
| 48. | Lani R, Hassandarvish P, Shu MH, Phoon WH, Chu JJ, Higgs S, et al. Antiviral activity of selected flavonoids against Chikungunya virus. Antiviral Res 2016;133:50-61. |
| 49. | Jain J, Kumar A, Narayanan V, Ramaswamy RS, Sathiyarajeswaran P, Devi MS, et al. Antiviral activity of ethanolic extract of Nilavembu Kudineer against Dengue and Chikungunya virus through in vitro evaluation. J Ayurveda Integr Med 2020;11:329-35. |
| 50. | Sharma V, Sharma M, Dhull D, Sharma Y, Kaushik S, Kaushik S. Zika virus: An emerging challenge to public health worldwide. Can J Microbiol 2020;66:87-98. |
| 51. | Subramanian S. Integrating medical doctors of modern and Indian system of medicine-unique opportunity for India along the lines of China. Indian J Pharmacol 2015;47:573-4. [ PUBMED] [Full text] |
| 52. | Loaiza-Cano V, Monsalve-Escudero LM, Filho CD, Martinez-Gutierrez M, Sousa DP. Antiviral role of phenolic compounds against dengue virus: A review. Biomolecules 2020;11:E11. |
| 53. | Qaddir I, Rasool N, Hussain W, Mahmood S. Computer-aided analysis of phytochemicals as potential dengue virus inhibitors based on molecular docking, ADMET and DFT studies. J Vector Borne Dis 2017;54:255-62. [ PUBMED] [Full text] |
| 54. | Raekiansyah M, Buerano CC, Luz MA, Morita K. Inhibitory effect of the green tea molecule EGCG against dengue virus infection. Arch Virol 2018;163:1649-55. |
| 55. | da Silva TF, Ferraz AC, Almeida LT, Caetano CC, Camini FC, Lima RL, et al. Antiviral effect of silymarin against Zika virus in vitro. Acta Trop 2020;211:105613. |
| 56. | Oo A, Teoh BT, Sam SS, Bakar SA, Zandi K. Baicalein and baicalin as Zika virus inhibitors. Arch Virol 2019;164:585-93. |
| 57. | Carrillo-Hernández MY, Ruiz-Saenz J, Villamizar LJ, Gómez-Rangel SY, Martínez-Gutierrez M. Co-circulation and simultaneous co-infection of dengue, Chikungunya, and Zika viruses in patients with febrile syndrome at the Colombian-Venezuelan border. BMC Infect Dis 2018;18:61. |
[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4]
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