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. 2023 Feb 8;112:154708. doi: 10.1016/j.phymed.2023.154708

Effect of andrographolide and deep eutectic solvent extracts of Andrographis paniculata on human coronavirus organ culture 43 (HCoV-OC43)

Jukrapun Komaikul a, Sasiporn Ruangdachsuwan a, Duangnapa Wanlayaporn a, Somnuek Palabodeewat a, Surat Punyahathaikul a, Theeraporn Churod a, Rattanathorn Choonong b, Tharita Kitisripanya c,⁎
PMCID: PMC9905047  PMID: 36805485

Abstract

Background

Andrographis paniculata (Burm. f.) Nees has demonstrated potential for treating infections caused by coronaviruses. However, no antiviral activity of andrographolide or A. paniculata extracts against human coronavirus organ culture 43 (HCoV-OC43) has been reported.

Purpose

This study aimed to evaluate the anti-HCoV-OC43 effect of andrographolide and A. paniculata as well as the correlation between andrographolide concentration and the anti-HCoV-OC43 activity of A. paniculata extracts.

Methods

This study evaluated and compared the in vitro anti-HCoV-OC43 activities of various A. paniculata extracts and andrographolide. To obtain A. paniculata extracts with different concentrations of andrographolide and its components, methanol and deep eutectic solvents (DES) were used to extract the aerial parts of A. paniculata. Andrographolide content was determined using UV-HPLC, and antiviral activity was assessed in HCT-8 colon cells.

Results

The methanol and five acidic DES (containing malic acid or citric acid) extracts of A. paniculata exerted anti-HCoV-OC43 activity. Antiviral activity had a moderately strong positive linear relationship (r = 0.7938) with andrographolide content. Although the methanol extract contained the highest andrographolide content (2.34 mg/ml), its anti-HCoV-OC43 activity was lower than that of the DES extracts containing lower andrographolide concentrations (0.92–1.46 mg/ml).

Conclusion

Methanol and the five acidic DES extracts of A. paniculata exhibited anti-HCoV-OC43 activity. However, the in vitro antiviral activity of A. paniculata extracts did not have a very strong positive linear relationship (r < 0.8) with andrographolide concentration in the extract. As a result, when comparing A. paniculata extracts, the anti-HCoV-OC43 test could provide a different result from the andrographolide concentration determination.

Keywords: Andrographis, Coronavirus, Antiviral activity, Herbal medicine, Deep eutectic solvent, Plant extract

Abbreviations: DES, deep eutectic solvents; DMEM, Dulbecco's modified eagle medium; HPLC, high-performance liquid chromatography; HCoV-OC43, human coronavirus organ culture 43; Non-SARS, non-severe acute respiratory syndrome; PBST, phosphate buffered saline; SARS, severe acute respiratory syndrome

Graphical abstract

Image, graphical abstract

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Introduction

Andrographis paniculata (Burm.f.) Nees (Acanthaceae) has been widely used as an Asian folk remedy for several generations (Jiang et al., 2021). In Thailand, A. paniculata registered herbal medicines have been available for the amelioration of colds, fevers, and associated symptoms. During the COVID-19 pandemic, standardized A. paniculata (aerial part crude powders in tablets or capsules) and standardized aerial parts of A. paniculata extracts at a dose of 180 mg (of andrographolide equivalent) per day were approved by Thailand's Health Ministry for treating asymptomatic or mild symptoms in COVID-19 patients (Intharuksa et al., 2022). A. paniculata is considered safe at therapeutic doses and rarely causes serious adverse effects (Worakunphanich et al., 2021). It has multiple bioactivities that could be helpful for treating viral infection and ameliorating related symptoms (Hossain et al., 2021), including anti-inflammatory, anti-oxidative (Mussard et al., 2020), antipyretic (Poolsup et al., 2004) and immunostimulation. Additionally, studies have indicated antiviral potentials of A. paniculata against human pathogenic viruses such as chikungunya, dengue (Panraksa et al., 2017), influenza (Chen et al., 2009; Yuan et al., 2016), and SARS-CoV-2. Andrographolide is the major active compound responsible for these bioactivities (Gupta et al., 2017). Thus, it was defined as a key bioactive marker that should be standardized for therapeutic use. However, A. paniculata extracts are complex, consisting of several other bioactive compounds, such as andrographolide derivatives, terpenoids, flavonoids, and iridoids, which can significantly affect their biological activities (Jiang et al., 2021; Wu et al., 2020). Sa-Ngiamsuntorn et al. (2021) reported that andrographolide exhibits in vitro anti-SARS-CoV-2 replication activity in human lung cells (Calu-3) with an IC50 of 0.034 µM, whereas 95% ethanol extract of A. paniculata aerial exhibits that activity with an IC50 of 0.036 µg/ml, which is equivalent to the extract containing 0.008 µM of andrographolide. The concentration of andrographolide in the extract required for the IC50 is 4.4-fold lower than that of andrographolide alone. Therefore, andrographolide quantification may not accurately indicate the efficacy of the A. paniculata product. To improve the standardization of a complex herbal medicine, a specific biological activity assay should be developed and applied (Liu et al., 2018), especially when the preparation or combination of an herbal drug is significantly changed compared with its traditional use.

Human coronavirus organ culture 43 (HCoV-OC43) is a non-SARS coronavirus belonging to the Betacoronavirus genus in the Coronaviridae family, such as SARS-CoV and SARS-CoV-2 (Liu et al., 2021). HCoV-OC43 generally causes a lower incidence of severe illnesses and fatalities than respiratory infections caused by other viruses (Jean et al., 2013). Therefore, this BSL-2 virus is suitable for testing the antiviral replication activity of broad-spectrum antiviral candidates (Weil et al., 2022). However, evidence of the anti-HCoV-OC43 activity of andrographolide and A. paniculata extracts is lacking.

Deep eutectic solvents (DES) are alternative solvents for phytochemical extraction that are eco-friendly, safe and reduce the toxicity of using organic solvents. Many studies have shown that DES are outstanding and promising solvents for sustainable and green extraction, which will lead to their novel application in the food, cosmetic and pharmaceutical industries (Dai et al., 2013). Moreover, DES improve the bioavailability of natural products (Sut et al., 2017).

In this study, we aimed to evaluate the activity of DES extracts against HCoV-OC43.

Materials and methods

Materials

A. paniculata (aerial part) dried powder was purchased from a local market in Ratchaburi, Thailand. Plant material was identified by Dr. Tharita Kitisripanya. The plant voucher specimen (PBM-006015) was deposited at the Herbarium of the Department of Pharmaceutical Botany, Faculty of Pharmacy, Mahidol University. The andrographolide standard (purity >98%) was obtained from the Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.

Preparation of DES

The DES composition used in this study is listed in Table 1 . To prepare each of these DES, appropriate amounts of hydrogen bond donor and hydrogen bond acceptor were accurately weighed, mixed, and heated at 60 °C. Then, deionized water was added to 30% w/w of the DES content. The mixture was stirred until a homogenous solution was obtained. The prepared DES were then maintain at room temperature.

Table 1.

Composition of DES.

Formula Composition Molar ratio
DES-1 choline chloride: glycerol 1:2
DES-2 choline chloride: dextrose 1:1
DES-3 choline chloride: malic acid 1:1
DES-4 choline chloride: citric acid 1:2
DES-5 choline chloride: citric acid 1:1
DES-6 proline: dextrose 1:1
DES-7 proline: citric acid 1:1
DES-8 proline: citric acid 1:2
DES-9 proline: malic acid 1:1
DES-10 proline: glycerol 1:1
DES-11 proline: glycerol 1:2
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Determination of andrographolide concentrations

A high-performance liquid chromatography (HPLC) method with slight modifications from the Thai Herbal Pharmacopoeia (2021) was used. Andrographolide content was determined using an HPLC Shimadzu LC-20AD equipped with an Acclaim 120 C18 (5 µm, 250 × 4.6 mm) column and a photodiode array detector at 224 nm. Elution was performed at a flow rate of 1.0 ml/min with water (solvent A) and methanol (solvent B) using the following gradient: 48% B (0–15 min), 48–80% B (15–20 min), 80% B (20–25 min), 80–48% B (25–30 min) and 48% B (30–35 min). The calibration curve was generated using five concentrations of standard andrographolide (12.5 to 200 µg/ml). The andrographolide content in the samples (μg/ml) was calculated from the peak area using a standard curve and the equation which was established as y = 47311x + 214,483.

Anti-HCoV-OC43 assay

Sample preparation

Methanol and DES were used as extraction solvents to obtain A. paniculata extracts containing different concentrations of andrographolide and its components. The extracts were diluted to ≤ 1% (v/v) of their solvent in DMEM containing 1% penicillin-streptomycin and 5% FBS (medium). Remdesivir and andrographolide were dissolved in DMSO, followed by the same diluent to ≤ 0.1% of DMSO in the medium. The samples were filtered through a 0.2 µm syringe filter and used as test substances for the test. The medium was used as a blank for untreated control.

Cell viability and in-cell ELISA

The experiments were performed in a biosafety level 2 laboratory. Forty microliters per well of HCoV-OC43 (ATCC, VR-1558™) at 25TCID50 was absorbed by confluent HCT-8 cells (ATCC, CCL-244™) in a 96-well-plate for 1 h at 33 ºC, 5% CO2. Then, 100 µl of the sample was added, mixed, and incubated for 4 days at 33ºC, with 5% CO2. For the cytotoxicity test, one part of PrestoBlue™ (Invitrogen, Life Technologies, CA, USA) per 10 parts of the culture medium was added and incubated for 2 h. To measure cell viability, the plate was read at 570 nm; 600 nm served as a reference wavelength. Then, the medium was removed and the plate was washed with 0.05% Tween 20 in phosphate buffered saline (PBST) twice. The cells were fixed with 80% acetone for 10 min.

To quantify the level of the infectious virus, in-cell ELISA was performed. The fixed cells were washed, blocked with 5% skim milk containing 0.5% triton-X100 in PBST, and incubated for 35 min. PBST was used as the washing buffer, and the incubation temperature was set to 37 °C. The plates were washed before adding 100 µl of 1:10,000 diluted HCoV-OC43 nucleocapsid antibody (40,643-T62, Sino Biological, Beijing, China) and incubated for 1 h. The cells were then washed and incubated with 100 µl of 1:20,000 diluted HRP-goat anti-rabbit IgG (Jackson ImmunoResearch, PA, USA) for 1 h. A 3,3′,5,5′-tetramethylbenzidine (TMB) kit (5120–0047, SeraCare, MA, USA) was used as the substrate. The plate was read at 450 nm, with 630 nm serving as the reference wavelength.

Statistical analysis

The HPLC experiments were performed in triplicate. Data are presented as the mean ± standard deviation (SD). The difference in the andrographolide contents between the samples extracted by different solvents was tested using one-way analysis of variance (ANOVA) and the Duncan's test at a p-value < 0.05. The stability of the extracts from the initial day and 1 month of age was tested by paired t-test at a p-value < 0.05 (PASW Statistics for Windows, version 18.0, SPSS Inc., Chicago, USA). The correlations between the IC50 against HCoV-OC43 and andrographolide content was assessed using Pearson's correlation test at a p-value < 0.05 (GraphPad Prism 9, CA, USA).

Results

Preparation of extracts

Eleven DES (1–11) were prepared for this study (Table 1). Choline chloride and proline were used as the hydrogen bond acceptors in the DES. Glycerol, dextrose, malic acid, and citric acid were selected as the hydrogen bond donors. All DES components were selected based on their safety for human use. Methanol extract of A. paniculata had the highest andrographolide content and antiviral activity as compared to that of ethanolic extract (3.23 ± 0.32% w/w of andrographolide, IC50 > 20 μM, respectively). Thus, the methanol extract was used to compare the anti-HCoV-OC43 test with A. paniculata DES extract.

The andrographolide content in the extracts obtained with 11 different DES (1–11) is shown in Table 2 . After ultrasonic-assisted extraction, the highest andrographolide yield was obtained using DES-8 and DES-4 (comprising proline and choline chloride, respectively). The resulting andrographolide content of all DES extracts was less than that of the methanol extract. The andrographolide content from DES extraction was more than 1% w/w except for DES-2, DES-6, and DES-10. According to the Thai Herbal Pharmacopoeia (2021), the andrographolide content in A. paniculata herbal preparations must be at least 1% w/w. In this study, this was applied as the cut-off point for selecting the andrographolide-enriched extracts. Eight DES extracts (DES-1; 3–5; 7–9, and −11) containing ≥1%w/w of andrographolide (equivalent to ≥ 0.68 mg/ml of andrographolide content) were included for further experiments.

Table 2.

Andrographolide content of A. paniculata extracts.

Solvent Andrographolide content (%w/w, mean ± SD) Andrographolide content (mg/ml, mean ± SD)
Methanol 3.45 ± 0.01a 2.34 ± 0.01a
DES-1 1.13 ± 0.03f,g 0.77 ± 0.02f,g
DES-2 0.74 ± 0.02h 0.50 ± 0.01h
DES-3 1.94 ± 0.08c,d 1.31 ± 0.05c,d
DES-4 2.19 ± 0.10b,c 1.46 ± 0.07b,c
DES-5 1.81 ± 0.11d 1.22 ± 0.07d
DES-6 0.62 ± 0.01h 0.41 ± 0.01h
DES-7 1.37 ± 0.01e,f 0.92 ± 0.01e,f
DES-8 2.27 ± 0.11b 1.55 ± 0.08b
DES-9 1.49 ± 0.13e 1.00 ± 0.09e
DES-10 0.90 ± 0.11 g,h 0.60 ± 0.07 g,h
DES-11 1.14 ± 0.15f,g 0.77 ± 0.10f,g
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Letters (a-h) indicate the level of significant difference between the groups (p < 0.05, one-way ANOVA, Duncan test).

Anti-HCoV-OC43 activity

The in vitro anti-HCoV-OC43 activities of the A. paniculata methanolic extract, eight DES extracts (DES-1; 3–5; 7–9, and −11) and andrographolide were evaluated. Each DES (without the A. paniculata sample) was tested as a blank, and no anti-HCoV-OC43 activity was detected. The 1%v/v concentrations of DES-5, −6, −7, −9, −10, −11 solvents caused cytotoxicity. The A. paniculata DES extracts containing DES-5, −6, −7, −9, or −11 at cytotoxic concentrations were excluded from the antiviral activity analysis. Remdesivir was used as a positive control.

Fig. 1 shows that five acidic DES extracts exerted greater anti-HCoV-OC43 activity than the methanol extract containing the highest andrographolide concentration. The five acidic DES extracts exerted greater anti-HCoV-OC43 activity than the methanol extract containing the higher andrographolide concentration (Fig. 1). The DES-9 extract showed no anti-HCoV-OC43 activity at 7.88 µM. The DES-1 and DES-11 extracts, which contained 0.77 mg/ml of andrographolide, did not show anti-HCoV-OC43 activity.

Fig. 1.

Fig. 1

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Relationship between the concentration of (A) remdesivir, (B) andrographolide, and (C – I) A. paniculata extracts and the percentage of inhibition of HCoV-OC43 (blue) and percentage of cell viability (red). Error bars represent standard deviation (n = 3).

Correlation between the anti-HCoV-OC43 activity and andrographolide content in the extracts

The correlation between the IC50 of each extract against HCoV-OC43 and the andrographolide concentration (%w/w) is shown in Fig. 2 . Based on the Pearson's correlation coefficient (r) value (0.7938), a moderately strong positive relationship (r values of 0.6–0.8) between the anti-HCoV-OC43 activity and andrographolide content in the extracts was found (p-value = 0.0331). As can be seen, the correlation was not very strong (r < 0.8). The methanol extract with the highest andrographolide concentration had lower antiviral activity (higher IC50) than the five extracts derived from acidic DES. The antiviral potential of the methanol and acidic DES extracts was also not ranked according to their andrographolide concentration.

Fig. 2.

Fig. 2

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Pearson's correlation between the IC50 against HCoV-OC43 and the andrographolide content (%w/w) of methanol and acidic DES extracts of A. paniculata.

Andrographolide stability in DES

Acidic DES were selected based on the anti-HCoV-OC43 test results and were used for the stability test. The A. paniculata extracts were stored at 4 °C for one month to evaluate the stability of andrographolide. As shown in Table 3 , the andrographolide contents in all extracts was not significantly degraded, except for DES-4. This indicates that the extracts remained stable during the experimental period and could be stable at 4 °C for at least 1 month.

Table 3.

Stability of andrographolide in solvents.

Solvent Andrographolide (mg/ml, mean ± SD)
Day 0 1 month
Methanol 2.34 ± 0.01 2.43 ± 0.00
DES-3 1.31 ± 0.05 1.18 ± 0.00
DES-4 1.46 ± 0.07 1.13 ± 0.00*
DES-5 1.22 ± 0.07 1.12 ± 0.00
DES-7 0.92 ± 0.01 0.82 ± 0.00
DES-8 1.55 ± 0.08 1.33 ± 0.01
DES-9 1.00 ± 0.09 0.77 ± 0.01
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Asterisk (*) indicates a significant decline in andrographolide content (p < 0.05, pair t-test).

Discussion

Colds and associated symptoms are commonly caused by coronaviruses, such as infections with non-severe acute respiratory syndrome (non-SARS)-related viruses or severe acute respiratory syndrome (SARS) coronaviruses (Calvo et al., 2020; Liu et al., 2021). The majority of cold patients with mild symptoms are commonly treated with supportive treatments such as nonsteroidal anti-inflammatory drugs, antihistamines, mucolytics, cough suppressants, and/or complementary medicines (Pietrusiewicz et al., 2021; Hui et al., 2022). To prevent severe symptoms of coronavirus infection, repurposing antiviral drugs has been an interesting strategy for the treatment of viral infections such as COVID-19, although their efficacy remains unclear (Martinez, 2022). The oral administration of A. paniculata alone or in combination has also been an option for treating respiratory infections (Jiang et al., 2021). To the best of our knowledge, this study found for the first time that four acidic DES (DES-3, DES-5, DES-7 and DES-8) were suitable for the preparation of A. paniculata extract, providing good extraction efficiency without reducing the stability of andrographolide or its antiviral activity. These can meet the standard requirements of the Thai Herbal Pharmacopoeia (2021) for A. paniculata extraction in terms of andrographolide content. The acidic DES did not significantly decrease the stability of andrographolide in the extract at 4 °C for at least 1 month. Furthermore, DES extracts inhibited HCoV-OC43 replication in the HCT-8 colon cells after the viral infection. The established DES extracts could be useful for further development of A. paniculata antiviral formulations such as mouth sprays or other oral dosage forms.

This is the first report of the anti-HCoV-OC43 properties of A. paniculata extracts and andrographolide. Nevertheless, it is unclear whether HCoV-OC43 infection or co-infection is associated with severe respiratory illness and hospitalization (Jean et al., 2013; Calvo et al., 2020). However, various strains of HCoV-OC43 have been commonly found in hospitalized patients with respiratory symptoms (Komabayashi et al., 2021; Kim et al., 2021), including a novel HCoV-OC43 genotype (Zhu et al., 2018). Keshavarz Valian et al. (2022) recently reported that HCoV-OC43 and SARS-CoV-2 have the same prevalence in children in Iran during the COVID-19 pandemic. It would be interesting to further determine whether A. paniculata products can reduce a patient's viral load, related symptoms, symptomatic infectious period, or reduce transmission risk.

In-cell ELISA for HCoV-OC43 determination is a potent method for providing support for antivirals that inhibit coronaviruses (Weil et al., 2022). The dose of A. paniculata has been recommended based on its andrographolide content (Intharuksa et al., 2022). It is unclear whether the dose of A. paniculata should be based on only andrographolide content. This study suggested that most A. paniculata extracts with high andrographolide content (1.37–3.45% w/w) had in vitro anti-HCoV-OC43 activity, whereas those with low andrographolide content (≤ 1.14% w/w) had no activity. However, the correlation between the antiviral activity and andrographolide content was not very strong. As a result, when comparing A. paniculata extracts, the anti-HCoV-OC43 test provided a different result from the andrographolide concentration determination. To improve and optimize the dosage of individual and complex A. paniculata extracts, further extraction development and in vivo or clinical studies could evaluate the antiviral activity or other related bioassays and compared with andrographolide concentrations.

Previously, citric acid and malic acid have been reported to possess inhibitory activity against the avian influenza virus (Chae et al., 2018). With addition of these organic acids to the ethanol, the residual virucidal activity persisted for at least 4 h (Turner et al., 2010). This study showed potentials of citric acid and malic acid as a component of acidic DES for the extraction of andrographolide and antiviral compounds from A. paniculata. However, acidic DES (containing citric acid and malic acid) without A. paniculata at the non-cytotoxic concentrations showed no antiviral activity (< 50% HCoV-OC43 inhibition) in this study.

Most phytochemical extracts derived from DES have been directly applied as food supplements, nutraceuticals, and cosmetics (Dai et al., 2013). A. paniculata extracts derived from acidic DES should be further developed as herbal formulations for the prevention of coronavirus infections.

Conclusion

Acidic DES could be an interesting solvent for A. paniculata extraction for antiviral uses. The results showed that the acidic DES extracts of A. paniculata and andrographolide exerted anti-HCoV-OC43 replication activities. The antiviral activity of the extracts was the result of a combination of compounds.

CRediT authorship contribution statement

Jukrapun Komaikul: Methodology, Formal analysis, Conceptualization, Investigation, Resources, Writing – original draft, Writing – review & editing, Project administration. Sasiporn Ruangdachsuwan: Investigation. Duangnapa Wanlayaporn: Investigation. Somnuek Palabodeewat: Investigation, Methodology. Surat Punyahathaikul: Investigation. Theeraporn Churod: Investigation. Rattanathorn Choonong: Formal analysis. Tharita Kitisripanya: Methodology, Formal analysis, Conceptualization, Investigation, Resources, Writing – original draft, Writing – review & editing, Project administration, Funding acquisition, Supervision.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

This research paper is supported by Specific League Funds from Mahidol University.

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.phymed.2023.154708.

Appendix. Supplementary materials

mmc1.docx (564KB, docx)

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