Virus Research 284 (2020) 197989

Contents lists available at ScienceDirect

Virus Research
journal homepage: www.elsevier.com/locate/virusres

Review

Natural product-derived phytochemicals as potential agents against T

coronaviruses: A review
Janice S. Mania,1, Joel B. Johnsona,1, Jason C. Steela, Daniel A. Broszczakb, Paul M. Neilsena,
Kerry B. Walsha, Mani Naikera,c,*
a
School of Health, Medical and Applied Sciences, CQUniversity, Bruce Hwy, North Rockhampton, QLD, Australia
b
Institute of Health & Biomedical Innovation (Q-Block), Queensland University of Technology, Kelvin Grove Campus, QLD, Australia
c
Centre for Indigenous Health Equity Research, CQUniversity, Bruce Hwy, North Rockhampton, QLD, Australia

A R T I C LE I N FO A B S T R A C T

Keywords: Coronaviruses are responsible for a growing economic, social and mortality burden, as the causative agent of
Coronaviridae diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), avian
Severe acute respiratory syndrome (SARS) infectious bronchitis virus (IBV) and COVID-19. However, there is a lack of effective antiviral agents for many
Middle East respiratory syndrome (MERS) coronavirus strains. Naturally existing compounds provide a wealth of chemical diversity, including antiviral
Traditional medicine
activity, and thus may have utility as therapeutic agents against coronaviral infections. The PubMed database
COVID-19
SARS-CoV-2
was searched for papers including the keywords coronavirus, SARS or MERS, as well as traditional medicine,
herbal, remedy or plants, with 55 primary research articles identified. The overwhelming majority of publica-
tions focussed on polar compounds. Compounds that show promise for the inhibition of coronavirus in humans
include scutellarein, silvestrol, tryptanthrin, saikosaponin B2, quercetin, myricetin, caffeic acid, psoralidin,
isobavachalcone, and lectins such as griffithsin. Other compounds such as lycorine may be suitable if a ther-
apeutic level of antiviral activity can be achieved without exceeding toxic plasma concentrations. It was noted
that the most promising small molecules identified as coronavirus inhibitors contained a conjugated fused ring
structure with the majority being classified as being polyphenols.

1. Introduction and HCoV-229E and the betacoronaviruses (βCoVs) HCoV-OC43

(Human CoV-OC43), HKU1 (Human CoV), SARS-CoV (Severe Acute
The dramatic change of events with the recent unprecedented cor- Respiratory Syndrome CoV), and MERS-CoV (Middle Eastern Re-
onavirus pandemic declared by the World Health Organisation (WHO) spiratory Syndrome CoV) (Lu et al., 2015). In the past two decades
has prompted an exponential increase of scientific interest in cor- there have been three epidemics caused by the betaCoVs, namely SARS
onaviruses globally. As of April 22nd 2020, the pandemic has resulted in 2002−03, MERS in 2012 and COVID-19, first identified in 2019
in 2,553,112infections, with 177,286 deaths worldwide, which con- (Yang et al., 2020b).
tinues to drastically increase as we write (https://www.who.int/ SARS-CoV emerged in 2002−03 in Southern China, causing a
emergencies/diseases/novel-coronavirus-2019). global threat and infecting more than 8000 people, with approximately
Coronaviruses (CoVs) belong to the family Coronaviridae, subfamily 800 fatalities recorded, largely in China and the surrounding regions
Coronavirinae and are large (genome size 26−32 kb; Wu et al., 2020a), (Lu et al., 2015; Paraskevis et al., 2020). MERS-CoV emerged in the
enveloped, positive-sense single-stranded ribonucleic acid (RNA) Middle East, spreading to several countries to infect close to 2300 in-
viruses that can infect both animals and humans (Fig. 1). Based on their dividuals, resulting in 845 deaths as of July 2019 (World Health
genotypic and serological characteristics, the viruses are subdivided Organization, 2019). The present CoV pandemic resulting from SARS-
into four genera: Alpha-, Beta-, Gamma-, and Deltacoronavirus (Chu CoV-2, which causes COVID-19 (coronavirus disease), was identified in
et al., 2020; Lu et al., 2015). At present, all identified CoVs that are Wuhan City, in the Hubei province of southern mainland China on the
capable of infecting humans belong to the first two genera. These in- 31st December 2019 (Sohrabi et al., 2020). The genome of SARS-CoV-2
clude the alphacoronaviruses (αCoVs) HCoV-NL63 (Human CoV-NL63) is approximately 70 % identical to that of SARS-CoV (Hui et al., 2020),

⁎
Corresponding author at: School of Health, Medical and Applied Sciences, CQUniversity, Bruce Hwy, North Rockhampton, QLD, Australia.
E-mail address: [email protected] (M. Naiker).
1
these authors contributed equally to the manuscript.

https://doi.org/10.1016/j.virusres.2020.197989
Received 3 April 2020; Received in revised form 24 April 2020; Accepted 24 April 2020
Available online 30 April 2020
0168-1702/ © 2020 Elsevier B.V. All rights reserved.
J.S. Mani, et al. Virus Research 284 (2020) 197989

Fig. 1. The general structure of a coronavirus (reproduced from Wikipedia under CC licence 4.0). E protein = envelope protein.

hence leading to its current name. isoquinoline alkaloid isolated from Cephaelis ipecacuanha and used as an
The major druggable targets of SARS-CoV-2 include 3-chymo- amoebicidal drug; quinine, derived from the bark of Cinchona trees; and
trypsin-like protease (3CLpro), papain like protease (PLpro), RNA-de- numerous other drugs modified from natural compounds, such aspirin,
pendent RNA polymerase, and spike (S) proteins (Wu et al., 2020b). morphine and paclitaxel, an antineoplastic drug used for the treatment
The S proteins interact directly with human angiotensin-converting of cancer (Ganjhu et al., 2015). Indeed, half of all drugs approved be-
enzyme (ACE) 2, allowing the virus to enter the cells. At present, no tween 1981 and 2014 were derived from or mimicked a natural com-
preventive vaccines or established antiviral therapies are available for pound (Newman and Cragg, 2016). Furthermore, in the current out-
coronaviruses (Sohrabi et al., 2020). However, several synthetic com- break of COVID-19, many patients appear to be turning to
pounds have shown promise, including hydroxychloroquine and cho- complementary or traditional medicinal therapies, albeit using them
loroquine phosphate (Cortegiani et al., 2020; Gao et al., 2020), which almost exclusively in conjunction with western medicine. For example,
act through several mechanisms, including alkalisation of the host cell one study suggested that almost 92 % of 135 hospitalised patients in
phagolysosomes. Newer antiviral medications such as lopinavir (Yao northeast Chonqing (China) received traditional Chinese medicine in
et al., 2020), remdesivir (Holshue et al., 2020; Wang et al., 2020), and addition to western medicine (Wan et al., 2020). However, based on the
arbidol (Khamitov et al., 2008) also show promise. Other suggested many studies conducted on this topic, it is hard to separate the potential
treatment options include lopinavir/ritonavir, nucleoside analogues, effects of, and interaction between, traditional Chinese herbal medicine
neuraminidase inhibitors, and peptide EK1 (Lu, 2020). A detailed list of and western medicine. Recent reviews have suggested that traditional
current and planned clinical trials investigating various drugs for the Chinese medicine could be used for the prevention (Luo et al., 2020) or
treatment of SARS-CoV-2 was provided by Pang et al. (2020), with treatment (Yang et al., 2020a) of COVID-19; while still acknowledging
updated results available from ClinicalTrials.gov (2020). that many studies involving clinical trials are poorly designed or con-
In addition, traditional herbal medicines and purified natural pro- trolled, and the choice of treatments is largely empirically based. As
ducts may guide the development of novel antiviral drugs. In other previous work has highlighted the potential of traditional Chinese
words, more efficient drugs can often be designed based on the struc- medicines as a source of potential novel drugs (Ling, 2020), we have
ture of natural compounds that exhibit the desired activity. Classic not included details on such studies investigating the antiviral activity
examples of this drug discovery pathway include emetine, an of remedies comprising portions of numerous plant species in this

2
J.S. Mani, et al. Virus Research 284 (2020) 197989

review. Rather, our aim is to collate data on the broad spectrum of method can then be forwarded on cell-based assays to assess their in
natural phytochemicals from individual plant species that may have vitro effectiveness and toxicity, before continuing to animal and clinical
therapeutic potential. trials.
Naturally occurring antiviral agents acting against general cor- Lung et al. (2020) virtually screened 83 compounds found in Chi-
onaviruses were briefly reviewed by Lin et al. (2014) six years ago, nese traditional medicines for activity against the RNA-dependent RNA
while more recent reviews by Pang et al. (2020) and Lu (2020) on polymerase of SARS-CoV-2, identifying theaflavin, an antioxidant
therapies for COVID-19 made only brief mention of natural therapeutics polyphenol, as a potential inhibitor. Similarly, Zhang et al. (2020)
and did not explore the active compounds or their mechanism of action. virtually screened 115 compounds found in Chinese traditional medi-
In light of the current COVID-19 pandemic, this review aims to gather cines, highlighting 13 for further studies. Several of these were natu-
and consolidate information on extracts and compound(s) derived from rally occurring polyphenolic compounds such as quercetin and
natural products which show potential antiviral bioactivity for the in- kaempferol, which have already received considerable interest for the
hibition of coronaviruses. It is hoped that the information presented treatment of other disease types (Cassidy et al., 2019; Khan et al., 2019;
may guide the naturally-derived drug discovery process in finding a Tome-Carneiro and Visioli, 2016).
treatment for SARS-CoV-2.
3.2. Inhibitors of SARS-CoV
2. Methods
Given the relatively large amount of research that has been per-
The PubMed database (www.ncbi.nlm.nih.gov/pubmed/) was used formed searching for inhibitors of SARS-CoV, antiviral agents that
to locate articles including the following combination of terms: (cor- successfully inhibit this viral strain may provide a good starting point
onavirus, SARS OR MERS) AND (traditional medicine, herbal, remedy for identifying compounds that are active against SARS-CoV-2.
OR plants). Papers primarily focussed on the antiviral activity of pre-
pared Chinese traditional medicines, which typically comprise multiple 3.2.1. Virtual screening
plant species, were considered out of scope of this review. All articles Several authors have utilised virtual computer docking models to
up to and including 25 March 2020 were considered, yielding a total of screen for potential compounds that could bind to and inhibit key
659 results. Two of the authors independently screened the results and proteins present in SARS-CoV (Liu and Zhou, 2005; Toney et al., 2004;
identified relevant articles, yielding a total of 35 primary articles on Wang et al., 2007), highlighting the potential antiviral activity of
human coronaviruses and 22 on animal coronaviruses were found to be compounds such as sabadinine and aurantiamide acetate. Compounds
pertinent and thus included in this review (total = 58 papers). Of these, may be screened against a number of binding sites in order to test for
two papers (6 %) were on SARS-CoV-2 (COVID-19). The majority of potential inhibition of coronaviruses; the main sites that are typically
studies on human coronaviruses (69 %; n = 24) included SARS-CoV, used are the chymotrypsin-like protease (3CLpro), papain like protease
with only 3 (9 %) including MERS-CoV and 8 (23 %) other human (PLpro), spike proteins and RNA-dependent RNA polymerase.
coronaviruses. It should be noted that one study included both SARS-
CoV and MERS-CoV (O’Keefe et al., 2010) while another included both 3.2.2. Compound library screening
MERS-CoV and HCoV-229E (Müller et al., 2018), hence these percen- Several large in vitro screening studies searching for inhibitory ac-
tages do not add to 100 %. tivity of naturally occurring compounds against SARS-CoV have been
performed, mainly on Chinese medicinal herbs (Li et al., 2005; Wang
3. et al., 2003). While the results highlight the potential of selected plant
extracts against SARS-CoV, they also demonstrate that such work can
Table 1 summarises the studies reporting the inhibition of various be akin to searching for a ‘needle in a haystack’. For example, Li et al.
human coronavirus strains using compounds derived from plant (2005) screened over 200 ethanol/chloroform extracts of Chinese
sources. The table is arranged by viral strain in order to better compare medicinal herbs and found only four (Lycoris radiata, Artemisia annua,
the bioactivity of compounds from different studies upon the same viral Pyrrosia lingua and Lindera aggregata) with moderate to high antiviral
genotypes. Where identified, the key compounds responsible for the activity using a CPE assay (EC50 values ranging from
antiviral activity and their identified mechanisms of action are pre- 2.4 ± 0.2–88.2 ± 7.7 μg/mL). Of these, a single compound (lycorine)
sented. It should be noted the term EC50 (effective concentration) ap- from one plant species (L. radiata) was earmarked as a potential drug
plies to cell-based assays, while IC50 (inhibitory concentration) applies candidate against SARS-CoV. The antiviral efficacy of lycorine was
to enzyme- or biochemical-based assays. quite high (EC50 of 15.7 ± 1.2 nM), with a selectivity index greater
than 900. Although the authors did not make mention of this fact, ly-
3.1. Inhibitors of SARS-CoV-2 (COVID-19) corine can cause toxic effects at low dosage levels (around 1 mg/kg in
dogs) (Kretzing et al., 2011), hence great caution would be required for
Few studies report on SARS-CoV-2, as expected given the short time further development of this compound as a drug candidate.
since its emergence. However, a number of studies report on use of Yu et al. (2012) screened the activity of a library of 64 naturally
computer modelling for screening purposes (Liu and Zhou, 2005; Lung occurring compounds against SARS-CoV helicase, which plays a key
et al., 2020; Toney et al., 2004; Wang et al., 2007; Zhang et al., 2020). role in the viral genome replication, transcription, and translation. The
Typically, these models determine the free binding of energy between a polyphenolics myricetin and scutellarein (Fig. 2) were identified as the
ligand and a receptor (Forli et al., 2016), with a lower free binding most promising candidates (IC50 values of 2.71 ± 0.19 and 0.86 ± 0.48
energy indicating a stronger bond between the ligand and receptor. μM, respectively). Although the antiviral activity of the compounds was
Although obtaining consistent results via different modelling ap- not assessed in cell-based assays, the authors did report that neither
proaches can be challenging (Aldeghi et al., 2016), computer modelling compound was toxic to normal (non-tumorigenic) breast epithelial
nevertheless allows for comparison of the relative binding affinity of cells. Myricetin is found in reasonably high concentrations in fruits such
bank of molecules toward the receptor in question. as cranberry (Häkkinen et al., 1999) as well as in several vegetables
In addition to reducing the high costs and length of time associated such as Calamus scipionum and garlic (Miean and Mohamed, 2001).
with physically screening large banks of compounds or plant extracts Scutellarein was isolated from Scutellaria baicalensis (Chinese Skullcap),
for bioactivity (Chen et al., 2017), the speed and versatility of this which has been traditionally used in the treatment of inflammation and
method may be particularly valuable for rapidly finding a potent in- respiratory infections, amongst other uses (Zhao et al., 2016). Both
hibitor of SARS-CoV-2. Compounds that are highlighted through this compounds were found to inhibit SARS-CoV helicase (nsP13) through

3
 Table 1
Studies reporting antiviral activity of natural products or isolates against human coronavirus strains.
Viral strain Assay method Plant species Plant part/ isolate EC50 or IC50 (μM unless SI Key compounds present (if identified) Biological action Reference
J.S. Mani, et al.

otherwise stated)

SARS-CoV-2 Computer modelling Present in: Camellia – ND ND Theaflavin Binding to RNA-dependent RNA (Lung et al.,
sinensis polymerase 2020)
SARS-CoV-2 Computer modelling Compounds previously n/a ND ND Betulinic acid Replication & 3CLpro (Zhang et al.,
identified in a range of Coumaroyltyramine PLpro & 3CLpro 2020)
Chinese traditional Cryptotanshinone PLpro & 3CLpro
medicines Desmethoxyreserpine Replication, 3CLpro & entry
Dihomo-c-linolenic 3CLpro
Dihydrotanshinone Entry & spike protein
Kaempferol PLpro & 3CLpro
Lignan Replication & 3CLpro
Moupinamide PLpro
N-cis-feruloyltyramine PLpro & 3CLpro
Quercetin PLpro & 3CLpro
Sugiol Replication & 3CLpro
Tanshinone IIa PLpro & 3CLpro
SARS-CoV CPE assay Boenninghausenia Isolated compound ∼450 ND Leptodactylone Not determined (Yang et al.,
sessilicarpa from ethanol extract 2007)
SARS-CoV CPE assay Hippeastrum hybrid Lectins isolated from 3.2 ± 2.8 > 31.3 Agglutinins: mannose-specific Inhibit viral attachment and (Keyaerts
Galanthus nivalis diaminopropane 6.2 ± 0.6 > 16.1 another target at end of et al., 2007)
Narcissus pseudonarcissus extracts 5.7 ± 4.4 > 17.5 replication cycle
Lycoris radiata 48 > 2.1
Allium porrum 0.45 ± 0.0 > 222.2
Allium ursinum 8 > 5.5
Cymbidium hybrid 18 ± 4 > 20

4
Listera ovata 4.9 ± 0.8 > 45.5
Epipactis helleborine 2.2 ± 1.3 > 55.5
Tulipa hybrid 1.8 ± 0.3 > 2.3
Morus nigra 22 ± 6 > 62.5
Nicotiana tabacum 1.6 ± 0.5 > 58.8 GlcNAc-specific
Urtica dioica 1.7 ± 0.3 > 76.9 (GlcNAc)n-specific
Morus nigra 1.3 ± 0.1 >2 Gal-specific
Cladastris lutea 50 ± 13 > 13.5 Man/Glc-specific
Polygonatum 7.4 ± 0.2 > 5.5 Gal/GalNAc-specific
multiflorum 18 ± 13 > 12.6 GalNAc(> Gal) specific
Iris hybrid 28 ± 11 22.7 GalNAcα(1.3)Gal > Gal
NAc > Gal-specific
2.2 ± 0.9 8.2
4.4 ± 3.1 16.2
Tulipa hybrid 3.4 ± 2.0 > 1.3 Man/GalNAc-specific
38 ± 0 (all μg/mL)
SARS-CoV (BJ001 CPE/MTS assay Artemisia annua 95 % EtOH extract 34.5−39.2 27−31 In L. radiata: lycorine Not determined (Li et al.,
and BJ006) Pyrrosia lingua Chloroform 40.5−43.2 55−59 2005)
Lindera aggregate 95 % EtOH 80.6−88.2 16−17
Lycoris radiata 95 % EtOH 2.1−2.4 (all μg/mL) 370−422
Isolated lycorine 48.8 ± 3.6 nM 954
Commercial lycorine 15.7 ± 1.2 nM 885
SARS-CoV BJ01 MTT cytotoxicity assay Galla chinensis Isolated compounds 10.6 14.622 Luteolin Binds with S2 subunit and (Yi et al.,
from 85 % ethanol 4.5 40.0 Tetra-O-galloyl-β-D-glucose preventing entry 2004)
extract
SARS-CoV FFM1 CPE assay Toona sinensis Boiled water extract 30−43 μg/mL 12−17 Not determined Not determined (Chen et al.,
of leaves 2008)
(continued on next page)
Virus Research 284 (2020) 197989
 Table 1 (continued)

Viral strain Assay method Plant species Plant part/ isolate EC50 or IC50 (μM unless SI Key compounds present (if identified) Biological action Reference
otherwise stated)
J.S. Mani, et al.

SARS-CoV FFM1 CPE assay Glycyrrhizin and Chemical standards 365 ± 12 > 65 Glycyrrhizin Not determined (Hoever
glycyrrhetinic acid found > 20 – 18β-glycyrrhetinic acid et al., 2005)
in: Glycyrrhiza radix
40 ± 13 > 75 Selected synthetic derivatives
35 ± 7 41
139 ± 20 2
8±2 6
50 ± 10 5
5±3 3
16 ± 1 4
SARS-CoV FFM1 CPE assay Laurus nobilis Essential oil 120 ± 1.2 μg/mL 4.2 L. nobilis: β-ocimene, 1,8-cineole, α- Inhibition of viral replication (Loizzo
pinene, β-pinene et al., 2008)
Thuja orientalis 130 ± 0.4 μg/mL 3.8 T. orientalis: α-pinene, δ-3-carene, α-
cedrol
SARS-CoV (Hong CPE assay Cibotium barometz 75 % ethanol 8.42- > 10 > 59.4 Not determined Not determined (Wen et al.,
Kong strain) Gentiana scabra extract 8.70 > 57.5 Secoiridoid & glycosides? 2011)
Dioscorea batatas 8.06 > 62.0 Polysaccharides?
Cassia tora 8.43 > 59.3 Emodin?
Taxillus chinensis 5.39 (all μg/mL) > 92.8 Quercetin?
SARS-CoV PUMC01 Plaque reduction assay Cinnamomi sp. Water extraction 10.7 ± 0.4 μg/mL (EtOH 16.9 Procyanidin A2 Early stage inhibition of viral (Zhuang
F5 followed by phase fraction) entry (clathrin-dependent et al., 2009)
extraction endocytosis pathway)
7.8 ± 0.3 μg/mL 23.1
(butanol fraction)
Isolated compound 29.9 ± 3.3 μM 37.35

5
SARS-CoV urbani Neutral red uptake assay Found in: Urtica dioica Chemical standard 2.6 ± 3.7 μg/mL 10.2 ± 5.6 Urtica dioica agglutinin Dose-dependent inhibition of (Kumaki
strain SARS-CoV-infected BALB/ used viral replication, likely in et al., 2011)
(200,300,592) c mouse model adsorption or penetration stages.
Binds to SARS-CoV spike
glycoprotein and N-
acetylglucosamine-like residues
on the glycosylated envelope
SARS-CoV CPE assay Found in Griffithsia sp. Chemical standard (μg/mL) Griffithsin Direct binding to surface (O’Keefe
Urbani strain used 0.61 > 164 envelope glycoprotein spike et al., 2010)
Tor-II strain 0.61 > 164
CuHK strain 0.78 > 128
Frank strain 1.19 > 83
SARS-CoV helicase Fluorometric helicase n/a Chemical standard 2.71 ± 0.19 ND Myricetin Inhibit ATPase activity of SARS- (Yu et al.,
nsP13 activity assay Scutettaria baicalensis Isolated compounds 0.86 ± 0.48 Scutellarein CoV helicase nsP13 2012)
SARS-CoV S protein Immunofluorescence assay Rheum officinale Water extracts (at ∼5 μg/mL ND Emodin Inhibited binding of S protein to (Ho et al.,
(IFA) 40 °C) of roots ACE2 2007)
Polygonum multiflorum Synthetic emodin 1−5 μg/mL
standard 200 μM
SARS-CoV 3CLpro Computer modelling Compounds from marine n/a n/a n/a 18 compounds identified: M3927, Inhibition of 3CLpro (Liu and
natural products M4367, M4890, M5410, M5789, Zhou, 2005)
database and traditional M6601, M6602, T1434, T1441,
Chense medicines T2826, T2831, T4744, T537, T5656,
database T6791, T8593, T3091, T5242
SARS-CoV CLpro Computer modelling Identified via computer n/a ND ND Sabadinine Inhibition of CoV protease (Toney et al.,
modelling. Found in: 2004)
Veratrum sabadilla
SARS-CoV CLpro Computer modelling for Found in: Artemisia n/a ND ND Aurantiamide acetate Inhibition of active pocket of CoV (Wang et al.,
compounds docking in annua protease 2007)
cathepsin-L protease
(continued on next page)
Virus Research 284 (2020) 197989
 Table 1 (continued)

Viral strain Assay method Plant species Plant part/ isolate EC50 or IC50 (μM unless SI Key compounds present (if identified) Biological action Reference
otherwise stated)
J.S. Mani, et al.

SARS-CoV 3CLpro 3CLpro cleavage assay Isatis indigotica Water extract of roots 53.8 ± 4.2 μg/mL > 92.9 Inhibition of 3CLpro (Lin et al.,
Isolated compounds 121 μM > 99.4 Sinigrin 2005)
300 μM 24.6 Indigo
115 μM 12.8 β-sitosterol
132 μM 87.8 Aloe-emodin
60 μM 45.3 Hesperetin
SARS-CoV 3CLpro 3CLpro inhibition test Rheum palmatum 75 % ethanol 13.76 ± 0.03 μg/mL ND Possibly anthraquinones Inhibition of 3CLpro (Luo et al.,
2009)
SARS-CoV CLpro CLpro inhibition assay Salvia miltiorrhiza Isolated compounds 89.1 ± 5.2 ND Tanshinone IIA Non-competitive enzyme (Park et al.,
from ethanol extract 24.8 ± 0.8 Tanshinone IIB isomerization inhibitor of 2012)
21.1 ± 0.8 Methyl tanshinonate protease (except for
226.7 ± 6.2 Cryptotanshinone rosmariquinone which exhibits
38.7 ± 8.2 Tanshinone I simple reversible slow-binding
14.4 ± 0.7 Dihydrotanshinone I inhibition)
21.1 ± 0.8 Rosmariquinone
SARS-CoV CLpro CLpro inhibition assay Torreya nucifera Isolated compounds 8.3 ± 1.2 ND Amentoflavone Non-competitive inhibition of (Ryu et al.,
from ethanol extract 72.3 ± 4.5 Bilobetin CoV CLpro 2010a)
32.0 ± 1.7 Ginkgetin
38.4 ± 0.2 Sciadopitysin
SARS-CoV CLpro CLpro inhibition assay Tripterygium regelii Isolated compounds 10.3 ± 0.2 ND Celastrol Competitive inhibition of CoV (Ryu et al.,
from 95 % methanol 5.5 ± 0.7 Pristimererin protease 2010b)
extract of bark 9.9 ± 0.1 Tingenone
2.6 ± 0.3 Iguesterin
SARS-CoV 3CLpro Fluorogenic 3CLpro Houttuynia cordata Boiled water extract ∼1000 μg/mL ND Not determined Minor 3CLpro inhibition. May (Lau et al.,
inhibition assay inhibit pivotal enzymes and 2008)

6
trigger negative feedback control
in immune systems
SARS-CoV PLpro PLpro inhibition assay Salvia miltiorrhiza Isolated compounds 1.6 ± 0.5 ND Tanshinone IIA Non-competitive enzyme (Park et al.,
from ethanol extract 10.7 ± 1.7 Tanshinone IIB isomerization inhibitor of 2012)
9.2 ± 2.8 Methyl tanshinonate protease (except for
0.8 ± 0.2 Cryptotanshinone rosmariquinone which exhibits
8.8 ± 0.4 Tanshinone I simple reversible slow-binding
4.9 ± 1.2 Dihydrotanshinone I inhibition)
30.0 ± 5.5 Rosmariquinone
SARS-CoV PLpro PLpro inhibition assay Broussonetia Isolated compounds 3.7 ± 1.6 ND 3′-(3-methylbut-2-enyl)-3′,4,7- Non-competitive inhibition of (Park et al.,
papyrifera from ethanol extract trihydroxyflavane CoV PLpro 2017)
SARS-CoV PLpro Fluorogenic PLpro Psoralea corylifolia Ethanol extract of 15 μg/mL Mixed inhibitor of SARS-CoV (Kim et al.,
inhibition assay seeds 38.4 ± 2.4 Bavachinin PLpro (isobavachalcone and 2014)
18.3 ± 1.1 Neobavaisoflavone psoralidin also reversible)
7.3 ± 0.8 Isobavachalcone
10.1 ± 1.2 4′-O-methylbavachalcone
4.2 ± 1.0 Psoralidin
32.3 ± 3.2 (rest in μM) Corylifol A
SARS-CoV urbani Fluorogenic protease Paulownia tomentosa Methanol extracts of 6.2 ± 0.04 ND Tomentin A Reversible, mixed-type (Cho et al.,
strain PLpro activity assay fruit 6.1 ± 0.02 Tomentin B (allosteric) inhibitors of PLpro 2013)
11.6 ± 0.13 Tomentin C
12.5 ± 0.22 Tomentin D
5.0 ± 0.06 Tomentin E
MERS-CoV EMC/ Luciferase assay Found in Griffithsia sp. Chemical standard/ ∼0.125 μg/mL ND Griffithsin Direct inhibition of protein spikes (Millet et al.,
2012 pure isolate used preventing viral binding 2016)
MERS-CoV EMC/ Cellular dual luciferase Found in Aglaia sp. Chemical standard 1.3 > 7690 Silvestrol Specific inhibitor of RNA helicase (Müller
2012 reporter assay used eIF4A et al., 2018)
MERS-COV PLpro PLpro inhibition assay Broussonetia papyrifera Isolated compounds 39.5 ± 5.1 ND Kazinol F Non-competitive inhibition of (Park et al.,
from ethanol extract 42.1 ± 5.0 Broussochalcone A CoV PLpro 2017)
(continued on next page)
Virus Research 284 (2020) 197989
 Table 1 (continued)

Viral strain Assay method Plant species Plant part/ isolate EC50 or IC50 (μM unless SI Key compounds present (if identified) Biological action Reference
otherwise stated)
J.S. Mani, et al.

HCoV-229E XTT assay Calophyllum blancoi Isolated compounds 3 ND Blancoxanthone Not determined (Shen et al.,
from acetone extract 15 Pyranojacareubin 2005)
of roots
HCoV-229E XTT assay Found in: Bupleurum Chemical standards 8.6 ± 0.3 26.6 Saikosaponin A Possible interference in early (Cheng
spp., Heteromorpha spp. used 1.7 ± 0.1 221.9 Saikosaponin B2 stage of viral replication, e.g. et al., 2006)
and Scrophularia 19.9 ± 0.1 19.2 Saikosaponin C absorption and penetration
scorodonia 13.2 ± 0.3 13.3 Saikosaponin D
HCov-229E CPE assay Pelargonium sidoides EPs® 7630 44.50 ± 15.84 μg/mL > 2.3 Not determined Possibly interference of virus (Michaelis
(proprietary extract surface resulting in viral et al., 2011)
using 11 % ethanol) inactivation
HCoV-229E Cellular dual luciferase Found in Aglaia sp. Chemical standard 3 > 3330 Silvestrol Specific inhibitor of RNA helicase (Müller
reporter assay used eIF4A et al., 2018)
HCoV-NL63 Plaque viricidal assay Strobilanthes cusia leaf Methanol extract 0.64 μg/mL > 156 Blocking viral RNA genome (Tsai et al.,
Isolated compounds 0.06 > 6600 Tryptanthrin synthesis and papain-like 2020)
2.09 > 191 Indigodole B protease 2 activity
HCoV-NL63 Virus yield reduction assay Sambucus formosana Ethanol extract of 1.17 ± 0.75 (μg/mL) ∼154 (Weng et al.,
stem 2019)
Isolated compounds 3.54 ± 0.77 > 141 Caffeic acid Inhibits cell docking
43.5 ± 6.0 > 11 Chlorogenic acid Not determined
71.5 ± 18.4 >7 Gallic acid Not determined
HCoV-OC43 CPE assay and neutral red Found in Griffithsia sp. Chemical standard 0.048−0.16 320- > 2100 Griffithsin Direct binding to surface (O’Keefe
HCoV-299E assay used 0.18−0.33 > 30−56 envelope glycoprotein spike et al., 2010)
HCoV-NL63 < 0.0032 (all μg/mL) > 3100
HCoV-OC43 MTS assay and qRT-PCR Found in: Stephania Chemical standards 0.33 ± 0.03 > 40.2 Tetrandrine Inhibit viral replication and (Kim et al.,
tetrandra and related used 1.01 ± 0.07 11.5 Fangchinoline expression of viral S and N 2019)

7
species 0.83 ± 0.07 13.6 Cepharanthine protein

CLpro = chymotrypsin-like protease; CPE assay = cytopathogenic effect assay; n/a = not applicable to this study; ND = no data; PLpro = papain-like protease.
Virus Research 284 (2020) 197989
J.S. Mani, et al. Virus Research 284 (2020) 197989

Fig. 2. The structure of selected naturally occurring compounds that demonstrate promising anti-coronavirus activity. (1) Quercetin (2) Quercetin 7-rhamnoside (3)
Myricetin (4) Psoralidin (5) Caffeic acid (6) Tryptanthrin (7) Lycorine (8) Scutellarein (9) Silvestrol (10) Saikosaponin B2 (11) Isobavachalcone (12) Griffithsin. As
annotated on (4), note the aromatic rings and substituted fused rings present in most compounds.

the inhibition of ATPase activity, but did not directly inhibit helicase mixed, reversible inhibitors of PLpro through a type I mechanism (i.e.
activity. This appeared to be the only publication identifying naturally preferentially bind to the free enzyme, rather than the enzyme substrate
occurring compounds as inhibitors of SARS-CoV helicase. complex) (Kim et al., 2014).
The need to isolate and synthesise more active agents as part of the
development pipeline was highlighted in a study by Runfeng et al. 3.2.4. Lectins
(2020). The authors reported that the Chinese herbal medicine Lian- Plant lectins, which are proteins that can bind specifically and re-
huaqingwen (comprised of a mixture of plant species) showed antiviral versibly to carbohydrate groups (Mitchell et al., 2017), are another
activity against SARS-CoV-2; however, the EC50 was quite high (∼411 group of naturally occurring compounds that may inhibit SARS-CoV.
μg/mL). For comparison, the commercial drug remdesivir showed an Lectins have shown promise as antiviral agents against viruses such as
EC50 of 0.651 μM (approx. 0.39 μg/mL) using the same assay (Runfeng influenza and herpes simplex virus (Hwang et al., 2020), as well as
et al., 2020). This also underscores the potential lack of potency in some Ebola (Covés-Datson et al., 2019; Michelow et al., 2011). Remarkably,
traditional medicines promoted for the treatment of coronavirus elevating the plasma levels of recombinant human mannose-binding
symptoms. lectin in mice allowed them to survive otherwise fatal Ebola infections
(Michelow et al., 2011). Keyaerts et al. (2007) screened the activity of a
3.2.3. Polyphenols broad range of plant lectins (33 in total) against SARS-CoV using a
One family of compounds that demonstrate antiviral activity across cytopathicity effect (CPE) assay, finding EC50 values as low as
a number of studies is the polyphenols. For example, quercetin (Fig. 3) 0.45 ± 0.08 μg/mL for Lycoris radiata agglutinin. Although the exact
showed an IC50 of 8.6 ± 3.2 μM against SARS-CoV PLpro (Park et al., mechanism of action was not determined, activity at the stage of viral
2017). No cell-based assay of antiviral activity was performed. Quer- attachment or the end of the infectious viral cycle were deemed to be
cetin (Fig. 2) is a flavonoid found in many foods, but in particularly the most likely targets. In clinical trials, other lectins have demon-
high levels in certain berries and herbs (Justesen and Knuthsen, 2001; strated reasonable to good tolerability (Petersen et al., 2006), hence
Kaack and Austed, 1998). As previously mentioned (section 3.2.2), the with further testing, they may prove to be one of the more promising
structurally similar polyphenolics myricetin and scutellarein (Fig. 2) classes of naturally derived compound(s) for the treatment of SARS-
display reasonable levels of inhibitory activity against SARS-CoV heli- CoV-2 and other coronavirus infections.
case (Yu et al., 2012).
Bioassay-guided fractionation of the ethanolic extract obtained from 3.2.5. Increasing potency via chemical modification
Psoralea corylifolia seeds has also identified polyphenolics as the Whilst many natural derived compounds show considerable promise
bioactive compounds responsible for the activity of this plant species for the inhibition of SARS-CoV and other human coronaviruses, few
against SARS-CoV PLpro (Kim et al., 2014). Furthermore, six phenolic approach the level of efficacy and/or selectivity required for commer-
phytochemicals were isolated from the ethanolic extracts - identified as cial drugs. For example, the calpain inhibitor MDL28170 has been
bavachinin, neobavaisoflavone, isobavachalcone, 4′-O-methylba- shown to have an IC50 value of just 2.5 nM (∼1 ng/mL) in its activity
vachalcone, psoralidin and corylifol A - with their antiviral activity against the SARS-CoV enzyme cathepsin-L (Simmons et al., 2005). Ca-
varying widely (IC50 values between 4.2–38.4 μM). Again, no cell-based thepsin-L is a cysteine protease which is an important lysosomal en-
antiviral assays were performed. Isobavachalcone and psoralidin dopeptidase enzyme involved in the initiation of protein degradation
(Fig. 2) showed the greatest antiviral activity, with both found to be (Sudhan and Siemann, 2015) and mediates entry and infection of SARS-

8
J.S. Mani, et al. Virus Research 284 (2020) 197989

Fig. 3. Possible binding sites of quercetin in SARS-CoV-2 3CLpro and tryptanthrin in PLpro. Docking was performed in AutoDock Vina 1.1.2 (Trott and Olson, 2010)
against target proteins generated by SWISS-MODEL (https://swissmodel.expasy.org/repository/species/2697049).

CoV in its host cells (Huang et al., 2006). Chemical modification of biochemical pathway. For example, the addition of glycosides and
naturally-derived compounds may be required to increase the potency specific amino acid residues to glycyrrhizin was performed with the
of their antiviral activity to levels suitable for therapeutic application. intent of increasing its affinity for the highly glycosylated spike proteins
For the drug discovery process, beginning with the understanding of the of SARS-CoV. With this in mind, future studies that identify an effective
structural conformity (i.e. structure including potential isomers) of the natural inhibitor of coronavirus should also consider the design and
naturally derived compound(s) can reduce timelines and greatly in- testing of potential modifications or synthetic derivatives that could
crease the chance of finding effective viral inhibitors. increase its desired activity.
Working on this principle, Hoever et al. (2005) found that mod-
ification of glycyrrhizin, naturally found in liquorice and previously 3.2.6. The significance of viral strains
used for the treatment of SARS-CoV (Haiying et al., 2003), could in- A difference in the efficacy of natural therapeutics, mirroring that
crease its viral inhibition activity. For example, adding 2-acetamido-β- observed for commercially/synthetically available drugs, has been ob-
D-glucopyranosylamine to the glycoside chain of glycyrrhizin increased served between coronavirus species/strains. For example, Park et al.
its antiviral activity in a CPE assay by 10-fold (decrease in EC50 from (2017) found that the compound 3′-(3-methylbut-2-enyl)-3′,4,7-trihy-
365 ± 12 μM to 40 ± 13 μM), through increased attraction to the S droxyflavane, isolated from Broussonetia papyrifera, showed good in-
proteins. Amides and conjugates with amino acid residues and free hibition of PLpro from SARS-CoV (IC50 of 3.7 ± 1.6 μM), but not
COOH increased activity of glycyrrhizin by up to 70-fold (EC50 for CPE against PLpro from MERS-CoV (IC50 of 112.5 ± 7.3 μM). In contrast,
assay ranging from 5 ± 3 μM to 139 ± 20 μM), albeit with significantly the polyphenolics kazinol F and broussochalcone A isolated from the
reduced selectivity. Cho et al. (2013) demonstrated that tomentins A–E same species showed better efficacy against MERS-CoV PLpro. Simi-
(all naturally occurring compounds) showed viral inhibition activity larly, O'Keefe et al. (2010) found that the efficacy of the compound
against SARS-CoV greater as compared to their non-geranylated pre- griffithsin against SARS-CoV was highest for the Urbani and Tor-II
cursor compounds. Similarly, quercetin-7-rhamnoside (Fig. 2) demon- strains (EC50 of 0.61 μg/mL using a CPE inhibition assay) and lowest for
strates over 100 times higher antiviral activity against an animal cor- the Frank strain (EC50 of 1.19 μg/mL). Griffithsin, isolated from the red
onavirus strain compared to its parent compound, quercetin (Choi alga Griffithsia sp., is a lectin possessing three large identical carbohy-
et al., 2009). drate-binding domains orientated as an equatorial triangle, which en-
While the examples of modifications presented here vary, it should able multivalent binding (O’Keefe et al., 2010). Although the source of
not be considered that substitutions are added in a random fashion, but these observed differences in the inhibition activity of griffithsin against
rather performed in the context of targeting a specific receptor or different SARS-CoV strains was not explored by O’Keefe et al. (2010), it

9
J.S. Mani, et al. Virus Research 284 (2020) 197989

may be attributable to genomic differences in the amino acid sequences Another recent study on HCoV-OC43 focussed on the antiviral ac-
of the spike proteins between SARS-CoV strains, leading to varying tivities of the bis-benzylisoquinoline alkaloids tetrandrine, fangchino-
multivalent interactions with the carbohydrates-binding domains and line, and cepharanthine (CPE assay EC50 values of 0.33 ± 0.03,
thus differing affinity for binding to the spike proteins. Nevertheless, 1.01 ± 0.07 and 0.83 ± 0.07 μM, respectively) (Kim et al., 2019).
these studies highlight the importance of conducting in vitro tests of These compounds were the primary bioactive phytochemicals identi-
potential naturally-derived therapeutics on SARS-CoV-2 prior to animal fied in Stephania tetrandra and related species. All compounds were
or clinical trials. found to inhibit virus-induced cell death, through suppressing viral
replication, expression of viral S and N proteins (nucleocapsid protein),
3.3. Inhibitors of MERS-CoV and the virus-induced host response. However, the effective inhibitory
concentrations were not reported for the inhibition of viral protein
Only a handful of studies have investigated the potential of natural expression or host response. In addition, tetrandrine activated the
products as therapeutic agents against MERS-CoV. Silvestrol (Fig. 2), a p38MAPK pathway in MRC-5 cells, improving the aforementioned host
phytochemical from Aglaia sp., was found to be a more potent inhibitor response.
of MERS-CoV replication (EC50 of 1.3 nM) (Müller et al., 2018). How- Weng et al. (2019) tested the ethanolic extracts of Sambucus for-
ever, no cell-based antiviral assays were performed. Silvestrol is a mosana (elderberry) stems against the human coronavirus strain HCoV-
specific inhibitor of RNA helicase eIF4A, thus inhibiting viral replica- NL63, finding quite high efficacy (EC50 of 1.17 ± 0.75 μg/mL) for viral
tion and leading to the inhibition of expression of CoV proteins and yield reduction. With further investigation of the phenolic composition
preventing the formation of replication/transcription complexes of the extracts and antiviral assays performed on the main individual
(Müller et al., 2018). phenolic acids present, caffeic acid (Fig. 2) was identified as the most
Griffithsin (Fig. 2), a 12.7 kDa lectin found in the Griffithsia genus potent compound present (EC50 of 3.54 ± 0.77 μM; or ∼0.64 ± 0.14
(red algae), is one of the most promising inhibitors of MERS-CoV. It μg/mL). Although no specific binding sites were identified, caffeic acid
comprises three carbohydrate-binding domains which allow it to bind was found to inhibit the attachment of HCoV to host cells, indicating
specifically to glycans on CoV protein spikes and inhibit viral attach- potential binding to S proteins. Caffeic acid has also been found to in-
ment to host cells, with high potency found in in vitro trials against hibit other viruses such as hepatitis B (Wang et al., 2009). Notably,
MERS-CoV (EC50 of ∼0.125 μM) (O'Keefe et al., 2010) and several extracts of Sambucus nigra (black elderberry), another species in the
HCoV strains (EC50 of 0.0032−0.33 μM) (Millet et al., 2016). Grif- same genus as S. formosana, have been commercialised for the treat-
fithsin also appears to have a low systematic toxicity, with its specificity ment of cold and flu symptoms. Therefore, it is likely that extracts from
index against HCoV cells (compared to human colorectal adenocarci- S. formosana would prove similarly nontoxic and suitable for human
noma or fibroblast cell lines) has been estimated at between 30–3100 use, although clinical trials would be required to confirm this. Never-
(O’Keefe et al., 2010), hence showing the potential to be considered as theless, the bioavailability/delivery mechanism of such extracts would
one of the prime candidates for animal and clinical trials against SARS- need to be considered in order to reach therapeutic plasma con-
CoV-2. centrations for viral inhibition (Wittemer et al., 2005).
Cheng et al. (2006) examined the anticoronaviral activity of sai-
3.4. Inhibitors of other human coronoviruses kosaponins (A, B2, C and D) and their mode of action against HCoV-
229E in vitro. Saikosaponins represent a group of pentacyclic triterpe-
A recent study highlighted the potential anti-HCoV-NL63 activity of noid derivatives, usually present as glycosides, that have been isolated
the methanolic extract of Strobilanthes cusia leaf and its major phyto- from medicinal plants such as Bupleurum spp., Heteromorpha spp. and
chemicals (Tsai et al., 2020). The S. cusia extract effectively reduced Scrophularia scorodonia, previously found to possess efficacy against
virus yield (EC50 = 0.64 μg/mL) in cells infected with HCoV-NL63 in a several viruses, including human immunodeficiency virus (HIV)
dose-dependent manner. Of the six key compounds isolated, purified (Chiang et al., 2003; Ushio and Abe, 1992). All saikosaponins tested
and identified via NMR spectroscopy, two exhibited the most potent showed good to moderate anti-coronavirus activity, with saikosaponin
antiviral activity against HCoV, namely tryptanthrin (Fig. 2), a natural B2(Fig. 2) showing the greatest potency (EC50 of 1.7 ± 0.1 μM). Sub-
alkaloid containing the basic indoloquinazoline moiety, and indigodole sequent time-of-addition studies indicated that saikosaponin B2 in-
B (5aR-ethyltryptanthrin), an indole alkaloid derivative. The EC50 va- hibited viral attachment and penetration. Interestingly, the same
lues against virus yield from infected cells were 1.52 μM and 2.60 μM compound has been found to inhibit hepatitis C entry (Lin et al., 2015)
for tryptanthrin and indigodole B, respectively. The increased antiviral as well as multidrug resistance-associated drug transporters present on
activity of tryptanthrin in comparison to indigodole B may result from the cell surface (Zhao et al., 2019), indicating that it has potential to
the double bond at C5a in the former, as compared to the additional display a broad spectrum of bioactivity. This may be advantageous in
ethyl moiety in the latter. This highlights that for compounds based on developing nations where hepatitis C prevalence is high (Pawlotsky,
a tryptanthrin structural conformity, addition of a double bond in the 2014).
quinazoline ring could significantly increase their antiviral activity. Finally, two compounds that have shown efficacy against MERS-
Tryptanthrin has previously been found to have a broad spectrum of CoV (section 3.3) also show promise against HCoV. Müller et al. (2018)
biological activities including anticancer, anti-inflammatory, anti- found that silvestrol (Fig. 2) inhibited the translation of HCoV-229E
protozoal, antiallergic, antioxidant and antimicrobial action (Kaur proteins, with an EC50 of 3 nM. A follow-up study confirmed that sil-
et al., 2017). Through manipulation of varying modes of time-of-addi- vestrol can inhibit HCoV-229E in an ex vivo bronchial epithelial cell
tion/removal assay, it was found that tryptanthrin prevented the early system, with its mechanism of action being the specific inhibition of
and late stages of HCoV-NL63 replication, particularly by blocking the RNA helicase eIF4A (Müller et al., 2020). Another compound active
viral RNA genome synthesis and papain-like protease 2 activity (Fig. 3), against MERS-CoV, griffithsin, also has shown great efficacy against
and inhibiting the post-entry stage of HCoV replication (Tsai et al., several HCoV strains (EC50 of 0.0032−0.33 μM) (Millet et al., 2016).
2020). Intriguingly, both tryptanthrin (EC50 = 0.06 μM) and indigodole This again underscores the prospect of exploring griffithsin for antiviral
B (EC50 = 2.09 μM) exhibited strong viricidal activity directly against activity against SAR-CoV-2.
HCoV-NL63. As the HCoV-NL63 spike protein (S protein) targets the
ACE2 receptor, showing a highly conserved sequence and structural 4. Animal coronaviruses
similarity to SARS-CoV and SARS-CoV-2 (Letko et al., 2020), tryptan-
thrin has the potential to be explored as a possible bioactive agent Animal coronavirus strains are responsible for severe morbidity
against SARS-CoV-2 and other human coronaviruses. events across a wide range of domestic animals and livestock, incurring

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J.S. Mani, et al. Virus Research 284 (2020) 197989

major economic demise worldwide (Jackwood et al., 2010; Lelesius (Hsieh et al., 2010). With an EC50 of just 0.0088 nM and a high se-
et al., 2019; McCutcheon et al., 1995). The genomic diversity, coupled lectivity index (> 218), this carbohydrate-binding protein out-
with the ability of coronaviruses to rapidly adapt and mutate, presents performed all synthetic antiviral agents tested for comparison purposes.
unique challenges in the development of novel antiviral agents, hence For example, the protease inhibitor nelfinavir displayed an EC50 of 8.19
exploring alternative methods of controlling these viruses could po- μM and a selectivity index of just 1.4. As with other agglutinins, Ga-
tentially be effective across many or all serotypes. As natural phyto- lanthus nivalis agglutinin binds to the spike and membrane proteins of
chemicals have been shown to have activity across a wide range of viral FCoV, preventing their attachment to the host cells.
pathogens (Chen et al., 2014), they form the basis of the studies re- McDonagh et al. (2014) conducted a screening study against 19
viewed here. The majority of plant-derived compounds considered in compounds, focusing on those demonstrated to have previous antiviral
this review are direct-targeting antivirals, acting through direct in- effects against coronaviruses or other RNA viruses. Several naturally
hibition of some part of the virus, such as proteases or spike proteins. occurring compounds were included in this study, such as quercetin,
For example, silvestrol prevents viral replication occurring through the curcumin, rutin, glycyrrhizic acid, hesperidin, hesperitin, baicalin and
specific inhibition of RNA helicase eIF4A (Müller et al., 2018), while artemisinin. However, none of these compounds reached EC50 at the
griffithsin binds directly to the S protein, preventing viral entry to the concentrations tested. Glycyrrhizic acid was the most promising,
host cell (O’Keefe et al., 2010). However, host-targeting antivirals form causing a 26.7 % reduction in CPE at a concentration of 25 μM. As only
another important group of antiviral compounds. For example, extracts a single concentration was tested for each compound (ranging from 10
of Cinnamomi sp. Inhibit the clathrin-dependent endocytosis pathway, to 50 μM, depending on the compound), further investigation of these
thus preventing viral entry to the host cells (Zhuang et al., 2009). Other compounds against FCoV is required.
host-targeting antiviral compounds may stimulate the immune response Theerawatanasirikul et al. (2020) adopted a computer-aided ap-
(Lau et al., 2008). proach to their screening study against feline infectious peritonitis virus
Table 2 presents a summary of studies reporting anti-viral activity of (FIPV), a mutated form of the parental enteric form of FCoV. Firstly,
plant-derived isolates against a range of animal coronavirus strains. compounds from a chemical library were virtually screened for poten-
Where available, the key compounds responsible for the antiviral ac- tial binding to the protease 3CL. The 15 most promising compounds
tivity and their mechanism of action are provided. were then evaluated in vitro using a protease inhibitor assay against
FIPV 3CLpro. Of the naturally occurring compounds tested, the lowest
4.1. Avian infectious bronchitis virus (IBV) IC50 values were shown by 7-methylluteolin (28.5 ± 4.2 μM) and stictic
acid (29.4 ± 4.6 μM). Quercetin 7-rhamnoside (Fig. 2) also showed
The antiviral activity of extracts from plant species against the avian moderate inhibition (IC50 of 77.2 ± 13.8 μM); however 7-benzyl lu-
IBV viral strains have been extensively studied (Chen et al., 2014; teolin and steviol showed no inhibition (IC50 > 500 μM). Subsequent
Jackwood et al., 2010; Lelesius et al., 2019; Li et al., 2011; Nguyen testing of the active compounds using a cytopathic effect (CPE) assay
et al., 2015; Yang et al., 2010, 2011; Yin et al., 2011). Considering all indicated that only stictic acid protected cells from viral-induced death
studies on avian IBV that have established the mechanism of viral in- (EC50 for pre-viral entry treatment of 16.24 ± 1.33 μM; selectivity
hibition, the main mechanisms of action appear to be through viral index of 23).
envelope disruption or interference with the spike protein (Table 2). A
notable exception are the terpenoid compounds 1,8-cineole, (-)-α- 4.3. Porcine endemic diarrhoea virus (PEDV)
pinene and (-)-β-pinene, which bind to the IBV nucleocapsid protein (N-
protein) (Yang et al., 2010, 2011), inhibiting its interaction with the Porcine endemic diarrhoea virus is another serious coronavirus from
viral genomic RNA and breaking the IBV replication cycle. These ob- the Alphacoronavirus group. Several studies have investigated the ac-
servations were reinforced by conformational models of the terpenoids tivity of phytochemicals against murine coronaviruses (strain MHV-
binding to the active site at the N terminus of the N protein, which A59), the most extensive of which were performed by Kim et al. (2008)
indicated that these compounds have the potential to bind strongly to and Kim et al. (2010). Nevertheless, none of the studies of this viral
five amino acid residues at this location (TyrA92, ProA134, PheA137, strain have conclusively managed to determine the specific compounds
AspA138 and TyrA140) (Yang et al., 2010, 2011). As these residues are responsible for viral inhibition, but rather suggested possible com-
highly conserved between IBV strains (Yang et al., 2010), these terpe- pounds or classes of compounds based on their abundance in the ex-
noids would be expected to show high efficacy against most or all IBV tracts tested. The low inhibitory concentrations (< 1 μg/mL) of extracts
strains, making them a sensible target for further research. obtained from Sophorae sp., Acanthopanacis sp. and Torilis sp. appear to
Nevertheless, the envelope protein (E protein) of avian IBV remains show significant potential. In particular, the high viral specificity (SI =
the key target for most researchers. The coronavirus E protein is in- 696) of Sophorae sp. root extracts suggests that it could be considered as
tegral to many stages of the viral life cycle, including assembly, bud- a prime candidate for future studies on the screening and isolation of
ding, envelope formation, and pathogenesis (Schoeman and Fielding, compounds from the aforementioned species. The authors suggested
2019). Interestingly, Chen et al. (2014) reported the inactivation of two that the antiviral activity of these three species are likely to be occur-
distinct enveloped viruses (avian IBV and influenza) following treat- ring through inhibition of RNA-dependent RNA polymerase or other
ment with Sambucus nigra extract, suggesting that S. nigra extract may protease activity.
have the potential to display a broad spectrum of antiviral effects Six studies considered natural agents active against porcine endemic
against many other enveloped viruses. Although the authors raised the diarrhea virus (PEDV), with the majority of these identifying the
possibility of synergistic action of inhibitory compounds within the compounds with for their antiviral activity. In particular, the anti-PEDV
extract, no fractionation, identification or characterisation of the activity of griffithsin and quercetin (Fig. 2) and its derivatives deserve
components was performed. However, flavonoids or lectins were sug- particular discussion, given that these compounds have also been found
gested as the likely aetiological agents of the antiviral activity. to have antiviral activity against human CoVs (Millet et al., 2016;
O'Keefe et al., 2010; Wen et al., 2011). Notably, quercetin was also one
4.2. Feline coronavirus of the compounds shortlisted by Zhang et al. (2020) in their virtual
screening of inhibitors of SARS-CoV-2 proteases. Against PEDV, quer-
Feline coronavirus is another coronavirus in the Alphacoronavirus cetin-7-rhamnoside, a disaccharide glucoside, provided 50 % inhibition
group, causing a fatal disease in cats with no effective antiviral treat- of viral activity at a concentration of just 0.03 μM, approximately 187
ments available. In one study, Galanthus nivalis agglutinin, another times lower than quercetin alone (Choi et al., 2009). Significantly, the
lectin, was identified as a potent inhibitor of feline coronavirus (FCoV) specificity of quercetin-7-rhamnoside was exceptionally high (SI =

11
 Table 2
Studies reporting antiviral activity of natural products or isolates against non-human coronavirus strains.
Viral strain Assay method Plant species Plant part/ isolate EC50 or IC50 (μM SI Key compounds present Biological action Reference
J.S. Mani, et al.

unless otherwise (if identified)

stated)

Avian IBV Plaque assay Alstonia scholaris Isolated from 50 % ethanol 35 > 2.8 Alstotide 1 As1: interferes with membrane (Nguyen et al., 2015)
extract 55 > 1.8 Alstotide 3 and spike proteins but not
nucleocapsid proteins
Avian IBV Beaudette CPE and plaque assays Sambucus nigra 70 % ethanol extract ND ND Possibly flavonols or Disrupts virion structure and (Chen et al., 2014)
strain lectins compromises membrane
integrity
Avian IBV Beaudette CPE assay n/a QR448(a) (emulsion of ∼1 × 10−4 ND Not determined Possibly disrupt viral membrane (Jackwood et al., 2010)
strain In vivo study in chickens oleoresins and essential dilution of or interfere with viral envelope
oils extract proteins involved in host cell
attachment
Avian IBV Beaudette CPE (MTT) assay Mentha piperita 40 % ethanol 0.004 μg/mL 67.5 Not determined Possibly direct inactivation of (Lelesius et al., 2019)
strain Thymus vulgaris extract 0.010 μg/mL 63.1 virus envelope structures
Desmodium canadense 0.017 μg/mL 17.1
Avian IBV Beaudette Plaque assay Houttuynia cordata H. cordata solution 0.97 mg/mL > 257 Main component: Not determined (Yin et al., 2011)
strain In ovo and in vivo trials (essential oils and sodium methyl-nonyl-ketone
chloride solution)
Avian IBV Gray strain MTT assay Found in numerous plants, Chemical standard used 0.61 ± 0.07 mM > 16.39 Eucalyptol (1,8-cineole) Interferes with binding between (Yang et al., 2010)
e.g eucalypts RNA and IBV nucleocapsid
protein
Avian IBV Gray strain MTT assay Found in coniferous trees. Chemical standards used 0.98 ± 0.25 mM > 10.20 (-)-α-pinene May suppress N-protein, (Yang et al., 2011)
Produced as by-products of 1.32 ± 0.11 mM > 7.58 (-)-β-pinene hindering binding process
the pulp industry between RNA and IBV N-protein
Avian IBV M41 CPE assay and RT-qPCR Found in: Forsythia suspensa Chemical standard used 0.64 mM ND Forsythoside A Not clear. Appears to affect cell (Li et al., 2011)

12
(complete signalling
inhibition)
Bovine coronavirus CPE assay Rosa nutkana Methanol extract < 200 μg/mL for ND R. nutkana: ND Not determined (McCutcheon et al., 1995)
(BCV) Amelanchier alnifolia (branches) both A. alnifolia: possibly
prunasin
FCoV NTU156 CPE assay Galanthus nivalis Commercial standard 0.0088 nM > 218 Galanthus nivalis Binds to spike and membrane (Hsieh et al., 2010)
agglutinin proteins
FIPV1146 and CPE assay n/a Commercial standards > > 10 ND Quercetin Not determined (McDonagh et al., 2014)
FECV1683 > > 10 Curcumin
(FCoVs) > > 25 Rutin
> > 25 Glycyrrhizic acid
> > 50 Hesperidin
> > 50 Hesperitin
> > 10 Baicalin
> > 25 Artemisinin
FIPV1146 (FCoV) Virtual screening followed by Found in: several lichen Commercial standards 29.4 ± 4.6 n/a Stictic acid Inhibition of 3CLpro (Theerawatanasirikul et al.,
3CLpro inhibition assay and plant species 28.5 ± 4.2 7-Methylluteolin 2020)
77.2 ± 13.8 Quercetin 7-rhamnoside
> 500 7-benzyl luteolin
> 500 Steviol
MHV-A59 Plaque assay Cimicifuga racemosa Methanol extracts 19.4 ± 7.0 12.3 Ferulic & isoferulic Inhibit replication of MHV (Kim et al., 2008)
acid?
Melia sp. 13.0 ± 1.4 25.6 Toosendanin?
Coptidis sp. 2.0 ± 0.5 34.9 Berberine?
Phellodendron sp. 10.4 ± 2.2 13.4 Protoberberine
alkaloids?
Sophora subprostrata 27.5 ± 1.1(μg/ 11.1 Matrine, oxymatrine,
mL) sophoranone &
sophocarpine?
(continued on next page)
Virus Research 284 (2020) 197989
 Table 2 (continued)

Viral strain Assay method Plant species Plant part/ isolate EC50 or IC50 (μM SI Key compounds present Biological action Reference
unless otherwise (if identified)
J.S. Mani, et al.

stated)

MHV-A59 Plaque assay Sophorae sp. Methanol 0.8 ± 0.2 696.0 Not determined Possibly inhibitors of RNA- (Kim et al., 2010)
Also inhibited MHV- Acanthopanacis sp. extracts 0.9 ± 0.1 188.9 dependent RNA polymerase or
JHM Sanguisorbae sp. 3.7 ± 1.4 105.0 other protease activity
Torilis sp. 0.8 ± 0.0(μg/ 195.6
mL)
MHV-A59 Plaque assay Punica granatum Pomegranate juice and ≥ 200 μg/mL ND Possibly polyphenols May interact with surface (Sundararajan et al., 2010)
ethanol/water extract of glycoproteins spikes
powder
MHV-A59 RT-qPCR Nigella sativa Ethanol extract ND ND Not determined Inhibits viral replication via (Ulasli et al., 2014)
Anthemis hyaline undetermined mechanism
Citrus sinensis
PEDV CPE assay Ziziphus jujuba Compounds isolated from 13.41 ± 1.13 > 30.0 Jubanine G Not determined (Kang et al., 2015)
methanol extract 4.49 ± 0.67 47.11 Jubanine H
6.17 ± 0.50 26.75 Nummularine B
PEDV CV 777 CPE assay Ginkgo biloba Polysaccharides purified 1.7 ± 1.3 μg/mL > 58.8 Mixture of Dose-dependent inhibition, (Lee et al., 2015)
from 98 % ethanol extract polysaccharides apparently at viral attachment
and entry steps
PEDV CV 777 CPE assay Houttuynia cordata Compound isolated from ND ND Quercetin 7-rhamnoside Uncertain. Doesn’t obstruct viral (Song et al., 2011)
methanol extract mRNA production or interact
directly with PEDV
PEDV CV 777 CPE assay Houttuynia cordata Compounds isolated from ∼0.03 ± 0.01 7143 Quercetin 7-rhamnoside Not determined (Choi et al., 2009)
methanol extract ∼5.6 ± 2.6 215 Quercetin
∼0.4 ± 0.4 370 Apigenin
∼0.7 ± 0.7 32.7 Luteolin

13
PEDV (KPEDV-9) CPE assay Prunus serrulata var. 80 % methanol extract 1.95 μg/mL ND Possibly polyphenols Not determined (Yook et al., 2010)
spontanea
PEDV (NJ-PEDV) Immunofluorescence assay Found in: Griffithsia sp. Purified compound used ∼0.08 ND Griffithsin Prevents viral attachment to (Li et al., 2019)
and RT-qPCR host cells

BCV = bovine coronavirus; CPE assay = cytopathogenic effect assay; FCoV = feline coronavirus; IBV = (avian) infectious bronchitis virus; MHV = mouse hepatitis virus; n/a = not applicable to this study; ND = no
data; PEDV = porcine epidemic diarrhoea virus.
Virus Research 284 (2020) 197989
J.S. Mani, et al. Virus Research 284 (2020) 197989

7143), indicating its potential for application in future animal or clin- Funding sources
ical trials. This study again highlights the importance of considering all
possible structural conformities of a compound, including glycosides, in This research did not receive any specific grant from funding
order to identify the most bioactive chemical species. Although the agencies in the public, commercial, or not-for-profit sectors.
mechanism of action was not determined for quercetin or quercetin-7-
rhamnoside against PEDV, previous computer modelling work has in- Declaration of Competing Interest
dicated that quercetin binds to and inhibits the SARS-CoV proteases
PLpro and 3CLpro (Zhang et al., 2020). As previously determined, The authors declare that no conflict of interest exists.
griffithsin binds to the spike protein of CoV, preventing attachment to
host cells (Millet et al., 2016; O'Keefe et al., 2010). References
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