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 unless otherwise stated)	SI	Key compounds present (if identified)	Biological action	Reference
Avian IBV	Plaque assay	Alstonia scholaris	Isolated from 50 % ethanol extract	35	>2.8	Alstotide 1	As1: interferes with membrane and spike proteins but not nucleocapsid proteins	(Nguyen et al., 2015)
				55	>1.8	Alstotide 3
Avian IBV Beaudette strain	CPE and plaque assays	Sambucus nigra	70 % ethanol extract	ND	ND	Possibly flavonols or lectins	Disrupts virion structure and compromises membrane integrity	(Chen et al., 2014)
Avian IBV Beaudette strain	CPE assay	n/a	QR448(a) (emulsion of oleoresins and essential oils	∼1 × 10−4 dilution of extract	ND	Not determined	Possibly disrupt viral membrane or interfere with viral envelope proteins involved in host cell attachment	(Jackwood et al., 2010)
	In vivo study in chickens
Avian IBV Beaudette strain	CPE (MTT) assay	Mentha piperita	40 % ethanol	0.004 μg/mL	67.5	Not determined	Possibly direct inactivation of virus envelope structures	(Lelesius et al., 2019)
		Thymus vulgaris	extract	0.010 μg/mL	63.1
		Desmodium canadense		0.017 μg/mL	17.1
Avian IBV Beaudette strain	Plaque assay	Houttuynia cordata	H. cordata solution (essential oils and sodium chloride solution)	0.97 mg/mL	>257	Main component: methyl-nonyl-ketone	Not determined	(Yin et al., 2011)
	In ovo and in vivo trials
Avian IBV Gray strain	MTT assay	Found in numerous plants, e.g eucalypts	Chemical standard used	0.61 ± 0.07 mM	>16.39	Eucalyptol (1,8-cineole)	Interferes with binding between RNA and IBV nucleocapsid protein	(Yang et al., 2010)
Avian IBV Gray strain	MTT assay	Found in coniferous trees. Produced as by-products of the pulp industry	Chemical standards used	0.98 ± 0.25 mM	>10.20	(-)-α-pinene	May suppress N-protein, hindering binding process between RNA and IBV N-protein	(Yang et al., 2011)
				1.32 ± 0.11 mM	>7.58	(-)-β-pinene
Avian IBV M41	CPE assay and RT-qPCR	Found in: Forsythia suspensa	Chemical standard used	0.64 mM (complete inhibition)	ND	Forsythoside A	Not clear. Appears to affect cell signalling	(Li et al., 2011)
Bovine coronavirus (BCV)	CPE assay	Rosa nutkana	Methanol extract (branches)	<200 μg/mL for both	ND	R. nutkana: ND	Not determined	(McCutcheon et al., 1995)
		Amelanchier alnifolia				A. alnifolia: possibly prunasin
FCoV NTU156	CPE assay	Galanthus nivalis	Commercial standard	0.0088 nM	>218	Galanthus nivalis agglutinin	Binds to spike and membrane proteins	(Hsieh et al., 2010)
FIPV1146 and FECV1683 (FCoVs)	CPE assay	n/a	Commercial standards	>>10	ND	Quercetin	Not determined	(McDonagh et al., 2014)
				>>10		Curcumin
				>>25		Rutin
				>>25		Glycyrrhizic acid
				>>50		Hesperidin
				>>50		Hesperitin
				>>10		Baicalin
				>>25		Artemisinin
FIPV1146 (FCoV)	Virtual screening followed by 3CLpro inhibition assay	Found in: several lichen and plant species	Commercial standards	29.4 ± 4.6	n/a	Stictic acid	Inhibition of 3CLpro	(Theerawatanasirikul et al., 2020)
				28.5 ± 4.2		7-Methylluteolin
				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 acid?	Inhibit replication of MHV	(Kim et al., 2008)
		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/mL)	11.1	Matrine, oxymatrine, sophoranone & sophocarpine?
MHV-A59	Plaque assay	Sophorae sp.	Methanol	0.8 ± 0.2	696.0	Not determined	Possibly inhibitors of RNA-dependent RNA polymerase or other protease activity	(Kim et al., 2010)
Also inhibited MHV-JHM		Acanthopanacis sp.	extracts	0.9 ± 0.1	188.9
		Sanguisorbae sp.		3.7 ± 1.4	105.0
		Torilis sp.		0.8 ± 0.0(μg/mL)	195.6
MHV-A59	Plaque assay	Punica granatum	Pomegranate juice and ethanol/water extract of powder	≥ 200 μg/mL	ND	Possibly polyphenols	May interact with surface glycoproteins spikes	(Sundararajan et al., 2010)
MHV-A59	RT-qPCR	Nigella sativa	Ethanol extract	ND	ND	Not determined	Inhibits viral replication via undetermined mechanism	(Ulasli et al., 2014)
		Anthemis hyaline
		Citrus sinensis
PEDV	CPE assay	Ziziphus jujuba	Compounds isolated from methanol extract	13.41 ± 1.13	>30.0	Jubanine G	Not determined	(Kang et al., 2015)
				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 from 98 % ethanol extract	1.7 ± 1.3 μg/mL	>58.8	Mixture of polysaccharides	Dose-dependent inhibition, apparently at viral attachment and entry steps	(Lee et al., 2015)
PEDV CV 777	CPE assay	Houttuynia cordata	Compound isolated from methanol extract	ND	ND	Quercetin 7-rhamnoside	Uncertain. Doesn’t obstruct viral mRNA production or interact directly with PEDV	(Song et al., 2011)
PEDV CV 777	CPE assay	Houttuynia cordata	Compounds isolated from methanol extract	∼0.03 ± 0.01	7143	Quercetin 7-rhamnoside	Not determined	(Choi et al., 2009)
				∼5.6 ± 2.6	215	Quercetin
				∼0.4 ± 0.4	370	Apigenin
				∼0.7 ± 0.7	32.7	Luteolin
PEDV (KPEDV-9)	CPE assay	Prunus serrulata var. spontanea	80 % methanol extract	1.95 μg/mL	ND	Possibly polyphenols	Not determined	(Yook et al., 2010)
PEDV (NJ-PEDV)	Immunofluorescence assay and RT-qPCR	Found in: Griffithsia sp.	Purified compound used	∼0.08	ND	Griffithsin	Prevents viral attachment to host cells	(Li et al., 2019)

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.