Table 1.

Natural products shown to have anti‐ZIKV effects

S/N	Compound name/Chemical structure/Source	Proposed mode of inhibition	IC50/EC50	ZIKV strain(s) tested	In vitro cell lines/in vivo animal models studied
Viral entry inhibitors
Inhibitors with direct virucidal effects
1	Labyrinthopeptin A1	Binds to viral membrane lipid phosphatidylethanolamine and disrupts viral membrane envelope	A1: 2.0 µM, 1.6 µM	976, H/PF/2013	In vitro: Huh‐7 1
			A2: 9.6 µM, 3.3 µM		In vivo: injected via i.v and i.p into 4‐week‐old male CD‐1 mice at 10 mg/kg1
	Labyrinthopeptin A2
	*Differences in amino acid residues are highlighted in blue. Lab: labionin; Dhb: didehydrobutyrine.
	Source: Actinomadura namibiensis DSM 6313
2	Delphinidin	Virucidal effect on virus particles	–	PA259459, MR766	In vitro: Vero  3
	Source: Various fruits  2
3	Epigallocatechin gallate (EGCG)	Inhibits NS2B‐NS3 viral protease, NS3 helicase, and has virucidal effect on virus particles	NS2B‐NS3pro: 0.73 ± 0.22 µM; 87 ± 1.2 µM	PA259459, MR766, Brazilian strain, Z16006	In vitro: Vero, 3 , 4 Vero E6, 5 purified ZIKV NS3 helicase, 6 NS2B‐NS3pro 4 , 7
			NS3 helicase: 295.7 nM		In silico molecular docking 8
	Source: Green tea		21.4 µM; 0.02 ± 0.003 µM
4	Baicalein	Inhibits a post‐entry step and has virucidal effect on virus particles	0.004 µM	PRVABC59	In vitro: Vero 9
					In silico molecular docking 9
	Source: Scutellaria baicalensis & Scutellaria lateriflora
5	Baicalin	Inhibits viral entry and has virucidal effect on virus particles	14 µM	PRVABC59	In vitro: Vero 9
					In silico molecular docking 9
	Source: Scutellaria baicalensis & Scutellaria lateriflora
6	Gossypol	Virucidal effect on virus particles	0.21–4.31 µM	PAN2016, R116265, PAN2015, FLR, R103451,	In vitro: Vero, purified E protein 11
	Source: Plants of the Gossypium genus 10		E protein: 7.12 µM	PRVABC59, PLCal_ZV, IbH 30656,
				MEX 2–81, MR766
7	Ginkgolic acid	Inhibits early stages of viral replication, possibly due to its virucidal activity	–	259249	In vitro: Vero 12
	Source: Ginkgo biloba
8	Emodin	Inhibits viral entry and has virucidal effect on virus particles	3.2 µM	Brazilian strain	In vitro: Vero, 14 Vero E6 15
	Source: Various plant species 13
9	Resveratrol	Inhibits a post‐entry step and has virucidal effect on virus particles	93% (1 log) reduction in foci	P6740, MR766, PE243	In vitro: Vero, 14 Huh‐7, 17 HTR‐8/SVneo, 18 Vero E6 18
	Source: Various plant species 16
10	Berberine	Virucidal effect on virus particles	39.06 µM	Brazilian strain	In vitro: Vero E6 15
	Source: Berberis vulgaris 19
11	Cephalotaxine	Inhibits post‐entry step of viral replication, possibly interfering with viral RNA translation. Virucidal effect also observed.	–	PRVABC59	In vitro: Vero, 20 A549 20
	Source: Cephalotaxus drupacea
Inhibitors targeting the viral entry process
12	Nanchangmycin	Blocks clathrin‐mediated endocytosis, inhibiting viral entry	0.1 µM	MR766, MEX 2‐81, FSS13025	In vitro: U2OS, 21 human brain microvascular endothelial cells, Vero, JEG‐3
	Source: Streptomyces nanchangensis
13	Quercetin	Inhibits NS2B‐NS3 viral protease and viral entry, possibly by targeting the virus particle itself or host cell surface proteins	NS2B‐NS3pro: 1.17 ± 0.22 µM; 2.4 ± 0.2 µM	MR766, Z16006	In vitro: Vero, 4 , 14 , 23 purified ZIKV NS2B‐NS3pro 4 , 24
	Source: Various plant species 22		2.3 ± 0.50 µM; 19.5 ± 4.8 µg/ml		In silico molecular docking 24
14	Kaempferide	Inhibits viral entry and NS2B‐NS3 viral protease	NS2B‐NS3pro: 7.18 ± 2.16 µM	Z16006	In vitro: Vero, 4 purified ZIKV NS2B‐NS3pro 4
	Source: Kaempferia galanga		5.83 ± 1.92 µM
15	Galangin	Inhibits viral entry and NS2B‐NS3 viral protease	NS2B‐NS3pro: 25.68 ± 9.17 µM	Z16006	In vitro: Vero, 4 purified ZIKV NS2B‐NS3pro 4
	Source: Alpinia officinarum Hance 25		14.36 ± 9.5 µM
16	Isoquercetin	Inhibits viral entry	1.2–1.3 µmol/L; 9.7–15.5 µM	PF‐25013‐18, MR766	In vitro: A549, 26 Huh‐7, 26 SH‐SY5Y, 26 Vero 27
				PLCal_ZV, PRVABC59	In vivo: injected via i.p. into
	Source: Various plant species 22				6–8‐week‐old male or female Ifnar1 −/− mice at 50 mg/kg 27
17	Ellagic acid	Reduces cell susceptibility to the virus by binding to host cell surface	30.86 µM	MR766, H/PF/2013	In vitro: Vero 28
	Source: Punica granatum
18	Curcumin	Inhibits viral entry or binding and NS2B‐NS3 viral protease	NS2B‐NS3pro: 3.5 ± 0.2 µM	PAN2016, R116265, PAN2015, FLR, R103451, PRVABC59, PLCal_ZV, IbH 30656, MEX 2–81, MR766, HD78788	In vitro: Vero E6, 11 HeLa, 29 purified ZIKV E protein, 11 NS2B‐NS3pro 24
	Source: Curcuma longa (Turmeric)		1.90 µM; 5.62–16.57 µM		In silico molecular docking 24
19	Digitonin	Inhibits viral entry	3.19–6.52 µM	PAN2016, R116265, PAN2015, FLR, R103451, PRVABC59, PLCal_ZV, IbH 30656, MEX 2–81, MR766	In vitro: Vero E6 11
	Source: Digitalis purpurea
20	Conessine	Inhibits virus‐cell attachment or a postentry step	7.18–11.60 µM	PAN2016,	In vitro: Vero E6 11
				R116265, PAN2015, FLR, R103451,
	Source: Holarrhena antidysenterica 30			PRVABC59, PLCal_ZV, IbH 30656, mosquitostrain MEX 2–81, rhesus macaque strain MR766
Viral replication inhibitors
21	Cavinafungin	Inhibits host endoplasmic reticulum signal peptidase, preventing viral replication	150 nM	FSS13025	In vitro: A549 31
	Source: Colispora cavincola
22	Sinefungin	Competitively binds to viral NS5 methyltransferase instead of S‐adenosylmethionine (SAM), prevents the methylation of the cap structure of viral RNA	1.18 ± 0.05 µM	H/PF/2013, MR766	In vitro: purified ZIKV NS5 methyltransferase 32 , 33
	Source: Streptomyces griseoleus
23	FV13	Multiple targets, likely to target a postgenome replication step	1.65 ± 0.86 µM	SV0010/15	In vitro: LLC/MK2 35
	Source: Chrysin‐derivative 34
24	FV14	–	1.39 ± 0.11 µM	SV0010/15	In vitro: LLC/MK2 35
	Source: Chrysin‐derivative 34
25	Pinocembrin	Inhibits viral RNA and envelope protein synthesis	17.4 µM	PRVABC59	In vitro: JEG‐3, 36 Huh‐7 36
	Source: Various plant species 37
26	Sophoraflavenone G (SFG)	Inhibits NS5 RdRp activity	22.61 µM	FSS13025	In vitro: primary human trophoblasts, 38 A549 38
	Source: Sophora flavescens
27	Cephaeline	Inhibits NS5 RdRp activity and disrupts host cell lysosomal function	NS5 RdRp: 976 nM	MR766, PRVABC59, FSS13025, Brazilian strain	In vitro: HEK293, 39 SNB‐19, Vero E6, purified ZIKV NS5 RdRp
	Source: Carapichea ipecacuanha		7.60 nM		In silico molecular docking 39
28	Emetine	Inhibits NS5 RdRp activity and disrupts host cell lysosomal function	NS5 RdRp: 121 nM	MR766, PRVABC59, FSS13025, Brazilian strain	In vitro: HEK293, 39 SNB‐19, Vero E6, purified ZIKV NS5 RdRp
	Source: Carapichea ipecacuanha		52.9 nM		In vivo: injected via i.p. into 3‐month‐old SJL male mice at 1 mg/kg/day, injected via i.p. into 6–7‐week‐old Ifnar1 −/− mice at 1 mg/kg 39
					In silico molecular docking 39
29	Lycorine	Inhibits NS5 RdRp activity	0.22–0. 39 µM	KU963796	In vitro: Vero, 40 A549, Huh‐7, purified ZIKV NS5 RdRp
					In vivo: intragastric administration in 4–5‐week‐old AG6 mice at 1–10 mg/kg 40
	Source: Various Amaryllidaceae species 41				In silico molecular docking 40
30	Silvestrol	Inhibits host cell factor eIF4A	–	976, H/PF/2013	In vitro: A549, 42 primary human hepatocytes
	Source: Aglaia foveolata
Inhibitors targeting the viral protease
31	Novobiocin	Competitively binds to NS2B‐NS3 viral protease	42.63 µM	PRVABC59	In vitro: Vero, 43 Huh‐7, purified ZIKV NS2B‐NS3pro
					In vivo: injected subcutaneously into dexamethasone‐immunosuppressed BALB/c mice at 100 mg/kg 43
	Source: Streptomyces niveus				In silico molecular docking 43
32	Apigenin	Noncompetitive inhibitor of NS2B‐NS3 viral protease	56.3 ± 0.9 µM	–	In vitro: purified ZIKV NS2B‐NS3pro 24
	Source: Apiaceae family plants 44				In silico molecular docking 24
33	Astragalin	Inhibits NS2B‐NS3 viral protease	112 ± 5.5 µM	–	In vitro: purified ZIKV NS2B‐NS3pro 7
	Source: Various plant species 45
34	Epicatechin gallate (ECG)	Inhibits NS2B‐NS3 viral protease	89 ± 1.6 µM	–	In vitro: purified ZIKV NS2B‐NS3pro 7
	Source: Green tea
35	Gallocatechin gallate (GCG)	Inhibits NS2B‐NS3 viral protease	99 ± 1.8 µM	–	In vitro: purified ZIKV NS2B‐NS3pro 7
	Source: Green tea
36	Isorhamnetin	Inhibits NS2B‐NS3 viral protease	15.5 ± 0.7 µM	–	In vitro: purified ZIKV NS2B‐NS3pro 24
	Source: Various plant species 46				In silico molecular docking 24
37	Luteolin	Noncompetitive (allosteric) inhibitor of NS2B‐NS3 viral protease	2.7 ± 0.3 µM; 53 ± 1.3 µM	–	In vitro: purified ZIKV NS2B‐NS3pro 7 , 24
	Source: Various plant species 47				In silico molecular docking 24
38	Myricetin	Inhibits NS2B‐NS3 viral protease via mixed inhibition	NS2B‐NS3 protease: 1.10–22 µM	Z16006	In vitro: Vero, 4 purified ZIKV NS2B‐NS3pro 4 , 7 , 24
	Source: Various plant species 22		0.58 ± 0.17 µM		In silico molecular docking 4 , 24
39	Rutin	Inhibits NS2B‐NS3 viral protease	104 ± 2.9 µM	–	In vitro: purified ZIKV NS2B‐NS3pro 7
	Source: Various plant species 48
40	Naringenin	Inhibits a postentry step, possible noncompetitive inhibitor of NS2B‐NS3 viral protease	58.79 µM	BR 2015/15261, BR 2015/15098, BR 2016/16288, PE243	In vitro: A549 49 , 50
					In silico molecular docking 50
	Source: Various citrus fruits 51
Inhibitors with unknown targets
41	Marinopyrrole derivative (Compound 1)	–	5.95 ± 0.72 µM	NR‐50210	In vitro: Vero 52
	Source: Actinomycete strain CNQ‐418 derivative
42	Kitasamycin	–	41.7 ± 10.1 µM	PE243	In vitro: Huh‐7 53
	Source: Streptomyces narbonensis
43	Hippeastrine hydrobromide (HH)	–	1.95 µM	MR766	In vitro: human pluripotent stem cell (hPSC)‐derived human cortical neural progenitor cells (hNPCs), human fetal‐like forebrain organoid model 54
	Source: Lycoris radiata				In vivo: injected subcutaneously in 6–8‐week‐old in severe combined immunodeficiency beige (SCID‐beige) mice at 100 mg/kg/day 54
44	18‐oxoferruginol	–	2.60 ± 0.07 µM	IMT17	In vitro: Vero 55
	Source: Sequoia sempervirens 56