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 otherwise stated)	SI	Key compounds present (if identified)	Biological action	Reference
SARS-CoV-2	Computer modelling	Present in: Camellia sinensis	–	ND	ND	Theaflavin	Binding to RNA-dependent RNA polymerase	(Lung et al., 2020)
SARS-CoV-2	Computer modelling	Compounds previously identified in a range of Chinese traditional medicines	n/a	ND	ND	Betulinic acid	Replication & 3CLpro	(Zhang et al., 2020)
						Coumaroyltyramine	PLpro & 3CLpro
						Cryptotanshinone	PLpro & 3CLpro
						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 sessilicarpa	Isolated compound from ethanol extract	∼450	ND	Leptodactylone	Not determined	(Yang et al., 2007)
SARS-CoV	CPE assay	Hippeastrum hybrid	Lectins isolated from diaminopropane extracts	3.2 ± 2.8	>31.3	Agglutinins: mannose-specific	Inhibit viral attachment and another target at end of replication cycle	(Keyaerts et al., 2007)
		Galanthus nivalis		6.2 ± 0.6	>16.1
		Narcissus pseudonarcissus		5.7 ± 4.4	>17.5
		Lycoris radiata		48	>2.1
		Allium porrum		0.45 ± 0.0	>222.2
		Allium ursinum		8	>5.5
		Cymbidium hybrid		18 ± 4	>20
		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 and BJ006)	CPE/MTS assay	Artemisia annua	95 % EtOH extract	34.5−39.2	27−31	In L. radiata: lycorine	Not determined	(Li et al., 2005)
		Pyrrosia lingua	Chloroform	40.5−43.2	55−59
		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 from 85 % ethanol extract	10.6	14.622	Luteolin	Binds with S2 subunit and preventing entry	(Yi et al., 2004)
				4.5	40.0	Tetra-O-galloyl-β-D-glucose
SARS-CoV FFM1	CPE assay	Toona sinensis	Boiled water extract of leaves	30−43 μg/mL	12−17	Not determined	Not determined	(Chen et al., 2008)
SARS-CoV FFM1	CPE assay	Glycyrrhizin and glycyrrhetinic acid found in: Glycyrrhiza radix	Chemical standards	365 ± 12	>65	Glycyrrhizin	Not determined	(Hoever et al., 2005)
				>20	–	18β-glycyrrhetinic acid
				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-pinene, β-pinene	Inhibition of viral replication	(Loizzo et al., 2008)
		Thuja orientalis		130 ± 0.4 μg/mL	3.8	T. orientalis: α-pinene, δ-3-carene, α-cedrol
SARS-CoV (Hong Kong strain)	CPE assay	Cibotium barometz	75 % ethanol	8.42->10	>59.4	Not determined	Not determined	(Wen et al., 2011)
		Gentiana scabra	extract	8.70	>57.5	Secoiridoid & glycosides?
		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 F5	Plaque reduction assay	Cinnamomi sp.	Water extraction followed by phase extraction	10.7 ± 0.4 μg/mL (EtOH fraction)	16.9	Procyanidin A2	Early stage inhibition of viral entry (clathrin-dependent endocytosis pathway)	(Zhuang et al., 2009)
				7.8 ± 0.3 μg/mL	23.1
				(butanol fraction)
			Isolated compound	29.9 ± 3.3 μM	37.35
SARS-CoV urbani strain (200,300,592)	Neutral red uptake assay SARS-CoV-infected BALB/c mouse model	Found in: Urtica dioica	Chemical standard used	2.6 ± 3.7 μg/mL	10.2 ± 5.6	Urtica dioica agglutinin	Dose-dependent inhibition of viral replication, likely in adsorption or penetration stages. Binds to SARS-CoV spike glycoprotein and N-acetylglucosamine-like residues on the glycosylated envelope	(Kumaki et al., 2011)
SARS-CoV	CPE assay	Found in Griffithsia sp.	Chemical standard used	(μg/mL)		Griffithsin	Direct binding to surface envelope glycoprotein spike	(O’Keefe et al., 2010)
Urbani strain				0.61	>164
Tor-II strain				0.61	>164
CuHK strain				0.78	>128
Frank strain				1.19	>83
SARS-CoV helicase nsP13	Fluorometric helicase activity assay	n/a	Chemical standard	2.71 ± 0.19	ND	Myricetin	Inhibit ATPase activity of SARS-CoV helicase nsP13	(Yu et al., 2012)
		Scutettaria baicalensis	Isolated compounds	0.86 ± 0.48		Scutellarein
SARS-CoV S protein	Immunofluorescence assay (IFA)	Rheum officinale	Water extracts (at 40 °C) of roots	∼5 μg/mL	ND	Emodin	Inhibited binding of S protein to ACE2	(Ho et al., 2007)
		Polygonum multiflorum	Synthetic emodin standard	1−5 μg/mL
				200 μM
SARS-CoV 3CLpro	Computer modelling	Compounds from marine natural products database and traditional Chense medicines database	n/a	n/a	n/a	18 compounds identified: M3927, M4367, M4890, M5410, M5789, M6601, M6602, T1434, T1441, T2826, T2831, T4744, T537, T5656, T6791, T8593, T3091, T5242	Inhibition of 3CLpro	(Liu and Zhou, 2005)
SARS-CoV CLpro	Computer modelling	Identified via computer modelling. Found in: Veratrum sabadilla	n/a	ND	ND	Sabadinine	Inhibition of CoV protease	(Toney et al., 2004)
SARS-CoV CLpro	Computer modelling for compounds docking in cathepsin-L protease	Found in: Artemisia annua	n/a	ND	ND	Aurantiamide acetate	Inhibition of active pocket of CoV protease	(Wang et al., 2007)
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., 2005)
			Isolated compounds	121 μM	>99.4	Sinigrin
				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 from ethanol extract	89.1 ± 5.2	ND	Tanshinone IIA	Non-competitive enzyme isomerization inhibitor of protease (except for rosmariquinone which exhibits simple reversible slow-binding inhibition)	(Park et al., 2012)
				24.8 ± 0.8		Tanshinone IIB
				21.1 ± 0.8		Methyl tanshinonate
				226.7 ± 6.2		Cryptotanshinone
				38.7 ± 8.2		Tanshinone I
				14.4 ± 0.7		Dihydrotanshinone I
				21.1 ± 0.8		Rosmariquinone
SARS-CoV CLpro	CLpro inhibition assay	Torreya nucifera	Isolated compounds from ethanol extract	8.3 ± 1.2	ND	Amentoflavone	Non-competitive inhibition of CoV CLpro	(Ryu et al., 2010a)
				72.3 ± 4.5		Bilobetin
				32.0 ± 1.7		Ginkgetin
				38.4 ± 0.2		Sciadopitysin
SARS-CoV CLpro	CLpro inhibition assay	Tripterygium regelii	Isolated compounds from 95 % methanol extract of bark	10.3 ± 0.2	ND	Celastrol	Competitive inhibition of CoV protease	(Ryu et al., 2010b)
				5.5 ± 0.7		Pristimererin
				9.9 ± 0.1		Tingenone
				2.6 ± 0.3		Iguesterin
SARS-CoV 3CLpro	Fluorogenic 3CLpro inhibition assay	Houttuynia cordata	Boiled water extract	∼1000 μg/mL	ND	Not determined	Minor 3CLpro inhibition. May inhibit pivotal enzymes and trigger negative feedback control in immune systems	(Lau et al., 2008)
SARS-CoV PLpro	PLpro inhibition assay	Salvia miltiorrhiza	Isolated compounds from ethanol extract	1.6 ± 0.5	ND	Tanshinone IIA	Non-competitive enzyme isomerization inhibitor of protease (except for rosmariquinone which exhibits simple reversible slow-binding inhibition)	(Park et al., 2012)
				10.7 ± 1.7		Tanshinone IIB
				9.2 ± 2.8		Methyl tanshinonate
				0.8 ± 0.2		Cryptotanshinone
				8.8 ± 0.4		Tanshinone I
				4.9 ± 1.2		Dihydrotanshinone I
				30.0 ± 5.5		Rosmariquinone
SARS-CoV PLpro	PLpro inhibition assay	Broussonetia papyrifera	Isolated compounds from ethanol extract	3.7 ± 1.6	ND	3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane	Non-competitive inhibition of CoV PLpro	(Park et al., 2017)
SARS-CoV PLpro	Fluorogenic PLpro inhibition assay	Psoralea corylifolia	Ethanol extract of seeds	15 μg/mL			Mixed inhibitor of SARS-CoV PLpro (isobavachalcone and psoralidin also reversible)	(Kim et al., 2014)
				38.4 ± 2.4		Bavachinin
				18.3 ± 1.1		Neobavaisoflavone
				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 strain PLpro	Fluorogenic protease activity assay	Paulownia tomentosa	Methanol extracts of fruit	6.2 ± 0.04	ND	Tomentin A	Reversible, mixed-type (allosteric) inhibitors of PLpro	(Cho et al., 2013)
				6.1 ± 0.02		Tomentin B
				11.6 ± 0.13		Tomentin C
				12.5 ± 0.22		Tomentin D
				5.0 ± 0.06		Tomentin E
MERS-CoV EMC/2012	Luciferase assay	Found in Griffithsia sp.	Chemical standard/pure isolate used	∼0.125 μg/mL	ND	Griffithsin	Direct inhibition of protein spikes preventing viral binding	(Millet et al., 2016)
MERS-CoV EMC/2012	Cellular dual luciferase reporter assay	Found in Aglaia sp.	Chemical standard used	1.3	>7690	Silvestrol	Specific inhibitor of RNA helicase eIF4A	(Müller et al., 2018)
MERS-COV PLpro	PLpro inhibition assay	Broussonetia papyrifera	Isolated compounds from ethanol extract	39.5 ± 5.1	ND	Kazinol F	Non-competitive inhibition of CoV PLpro	(Park et al., 2017)
				42.1 ± 5.0		Broussochalcone A
HCoV-229E	XTT assay	Calophyllum blancoi	Isolated compounds from acetone extract of roots	3	ND	Blancoxanthone	Not determined	(Shen et al., 2005)
				15		Pyranojacareubin
HCoV-229E	XTT assay	Found in: Bupleurum spp., Heteromorpha spp. and Scrophularia scorodonia	Chemical standards used	8.6 ± 0.3	26.6	Saikosaponin A	Possible interference in early stage of viral replication, e.g. absorption and penetration	(Cheng et al., 2006)
				1.7 ± 0.1	221.9	Saikosaponin B2
				19.9 ± 0.1	19.2	Saikosaponin C
				13.2 ± 0.3	13.3	Saikosaponin D
HCov-229E	CPE assay	Pelargonium sidoides	EPs® 7630 (proprietary extract using 11 % ethanol)	44.50 ± 15.84 μg/mL	>2.3	Not determined	Possibly interference of virus surface resulting in viral inactivation	(Michaelis et al., 2011)
HCoV-229E	Cellular dual luciferase reporter assay	Found in Aglaia sp.	Chemical standard used	3	>3330	Silvestrol	Specific inhibitor of RNA helicase eIF4A	(Müller et al., 2018)
HCoV-NL63	Plaque viricidal assay	Strobilanthes cusia leaf	Methanol extract	0.64 μg/mL	>156		Blocking viral RNA genome synthesis and papain-like protease 2 activity	(Tsai et al., 2020)
			Isolated compounds	0.06	>6600	Tryptanthrin
				2.09	>191	Indigodole B
HCoV-NL63	Virus yield reduction assay	Sambucus formosana	Ethanol extract of stem	1.17 ± 0.75 (μg/mL)	∼154			(Weng et al., 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 assay	Found in Griffithsia sp.	Chemical standard used	0.048−0.16	320->2100	Griffithsin	Direct binding to surface envelope glycoprotein spike	(O’Keefe et al., 2010)
HCoV-299E				0.18−0.33	>30−56
HCoV-NL63				<0.0032 (all μg/mL)	>3100
HCoV-OC43	MTS assay and qRT-PCR	Found in: Stephania tetrandra and related species	Chemical standards used	0.33 ± 0.03	>40.2	Tetrandrine	Inhibit viral replication and expression of viral S and N protein	(Kim et al., 2019)
				1.01 ± 0.07	11.5	Fangchinoline
				0.83 ± 0.07	13.6	Cepharanthine

CLpro  = chymotrypsin-like protease; CPE assay = cytopathogenic effect assay; n/a = not applicable to this study; ND = no data; PLpro = papain-like protease.