药学学报

No.	Compound	Antiviral species	Mechanism of action	Ref.
1	Artemisinin	SARS-CoV-2	Artemisinin derivatives in preventing the interaction between the virus' SProtein and hACE2 receptor via selectively interacting with the Lys353 binding hotspot of SProtein	[4]
2	Rhein	SARS-CoV-2	Exhibited high inhibitory effect on ACE2	[5]
3	Forsythoside A	SARS-CoV-2
4	Withaferin A	SARS-CoV-2	Significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells	[6]
5	Piperine	SARS-CoV-2
6	Mangiferin	SARS-CoV-2
7	Thebaine	SARS-CoV-2
8	Berberine	SARS-CoV-2
9	Andrographolide	SARS-CoV-2
10	Nimbin	SARS-CoV-2
11	Salvianolic acid	SARS-CoV-2	Salvianolic acid C potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein	[7]
12	Quercetin	IAV	Quercetin showed interaction with the HA2 subunit	[8]
13	18β-Glycyrrhetinic acid	HRSV	Decreased HRSV infection largely by inhibiting viral attachment, internalization, and by stimulating IFN secretion	[10]
14	Chlorogenic acid	SARS-CoV-2	Chlorogenic acid could stably combine with Gln325 and Gln42/Asp38 in ACE2, respectively, which hindered the combination between S-protein and ACE2	[11]
15	Puerarin	SARS-CoV-2	Puerarin had good binding activity with ACE2 and hydrolase of SARS-CoV-2	[12]
16	Luteolin	SARS-CoV-2	Embrace satisfactory binding to ACE2, and also had good binding to core targets	[13-15]
17	β-Sitosterol	SARS-CoV-2
18	Formononetin	SARS-CoV-2
19	Icariine	SARS-CoV-2
20	Palmitic acid	SARS-CoV-2	These volatile oil components had good binding activity with ACE2	[16]
21	Linoleic acid	SARS-CoV-2
22	Anisic acid	SARS-CoV-2
23	Hesperidin	SARS-CoV-2	They had good affinity with the core target ACE2 of SARS-CoV-2	[17]
24	Naringin	SARS-CoV-2
25	Amygdalin	SARS-CoV-2
26	Liquiritin	SARS-CoV-2
27	Licoisoflavone	SARS-CoV-2
28	Curcumin	SARS-CoV-2	A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin as SARS-CoV-2 spike protein inhibitors	[18, 19]
29	Fortunellin	SARS-CoV-2	It could be well embedded into the active pocket of ACE2-SARS-CoV-2 S protein	[20]
30	Cannabigerolic acid	SARS-CoV-2	Prevent infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells	[21]
31	Tetrahydrocannabinolic acid	SARS-CoV-2
32	Cannabidiolic acid	SARS-CoV-2
33	1, 2, 3, 4, 6-Vegalacyl glucose	SARS-CoV-2	A safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors	[22]
34	Gingerol	SARS-CoV-2	Inhibited the viral protein of both wild-type and mutated S-protein of SARS-CoV-2	[23]
35	Thymol	SARS-CoV-2
36	Thymohydroquinone	SARS-CoV-2
37	Cyclocurcumin	SARS-CoV-2
38	Epigallocatechin gallate	SARS-CoV-2	The inhibitor blocked binding to S-protein in a dose-dependent manner	[24]
39	Quinoline-2-carboxylic acids	SARS-CoV-2	Blocked the interaction between SARS-CoV-2 RBD and ACE2 in a dose-dependent manner	[25]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Artemisinin

SARS-CoV-2

Artemisinin derivatives in preventing the interaction between the virus' SProtein and hACE2 receptor via selectively interacting with the Lys353 binding hotspot of SProtein

[4]

Rhein

SARS-CoV-2

Exhibited high inhibitory effect on ACE2

[5]

Forsythoside A

SARS-CoV-2

Withaferin A

SARS-CoV-2

Significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells

[6]

Piperine

SARS-CoV-2

Mangiferin

SARS-CoV-2

Thebaine

SARS-CoV-2

Berberine

SARS-CoV-2

Andrographolide

SARS-CoV-2

Nimbin

SARS-CoV-2

Salvianolic acid

SARS-CoV-2

Salvianolic acid C potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein

[7]

Quercetin

IAV

Quercetin showed interaction with the HA2 subunit

[8]

18β-Glycyrrhetinic acid

HRSV

Decreased HRSV infection largely by inhibiting viral attachment, internalization, and by stimulating IFN secretion

[10]

Chlorogenic acid

SARS-CoV-2

Chlorogenic acid could stably combine with Gln325 and Gln42/Asp38 in ACE2, respectively, which hindered the combination between S-protein and ACE2

[11]

Puerarin

SARS-CoV-2

Puerarin had good binding activity with ACE2 and hydrolase of SARS-CoV-2

[12]

Luteolin

SARS-CoV-2

Embrace satisfactory binding to ACE2, and also had good binding to core targets

[13-15]

β-Sitosterol

SARS-CoV-2

Formononetin

SARS-CoV-2

Icariine

SARS-CoV-2

Palmitic acid

SARS-CoV-2

These volatile oil components had good binding activity with ACE2

[16]

Linoleic acid

SARS-CoV-2

Anisic acid

SARS-CoV-2

Hesperidin

SARS-CoV-2

They had good affinity with the core target ACE2 of SARS-CoV-2

[17]

Naringin

SARS-CoV-2

Amygdalin

SARS-CoV-2

Liquiritin

SARS-CoV-2

Licoisoflavone

SARS-CoV-2

Curcumin

SARS-CoV-2

A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin as SARS-CoV-2 spike protein inhibitors

[18, 19]

Fortunellin

SARS-CoV-2

It could be well embedded into the active pocket of ACE2-SARS-CoV-2 S protein

[20]

Cannabigerolic acid

SARS-CoV-2

Prevent infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells

[21]

Tetrahydrocannabinolic acid

SARS-CoV-2

Cannabidiolic acid

SARS-CoV-2

1, 2, 3, 4, 6-Vegalacyl glucose

SARS-CoV-2

A safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors

[22]

Gingerol

SARS-CoV-2

Inhibited the viral protein of both wild-type and mutated S-protein of SARS-CoV-2

[23]

Thymol

SARS-CoV-2

Thymohydroquinone

SARS-CoV-2

Cyclocurcumin

SARS-CoV-2

Epigallocatechin gallate

SARS-CoV-2

The inhibitor blocked binding to S-protein in a dose-dependent manner

[24]

Quinoline-2-carboxylic acids

SARS-CoV-2

Blocked the interaction between SARS-CoV-2 RBD and ACE2 in a dose-dependent manner

[25]

No.	Compound	Antiviral species	Mechanism of action	Ref.
1	Artemisinin	SARS-CoV-2	Artemisinin derivatives in preventing the interaction between the virus' SProtein and hACE2 receptor via selectively interacting with the Lys353 binding hotspot of SProtein	[4]
2	Rhein	SARS-CoV-2	Exhibited high inhibitory effect on ACE2	[5]
3	Forsythoside A	SARS-CoV-2
4	Withaferin A	SARS-CoV-2	Significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells	[6]
5	Piperine	SARS-CoV-2
6	Mangiferin	SARS-CoV-2
7	Thebaine	SARS-CoV-2
8	Berberine	SARS-CoV-2
9	Andrographolide	SARS-CoV-2
10	Nimbin	SARS-CoV-2
11	Salvianolic acid	SARS-CoV-2	Salvianolic acid C potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein	[7]
12	Quercetin	IAV	Quercetin showed interaction with the HA2 subunit	[8]
13	18β-Glycyrrhetinic acid	HRSV	Decreased HRSV infection largely by inhibiting viral attachment, internalization, and by stimulating IFN secretion	[10]
14	Chlorogenic acid	SARS-CoV-2	Chlorogenic acid could stably combine with Gln325 and Gln42/Asp38 in ACE2, respectively, which hindered the combination between S-protein and ACE2	[11]
15	Puerarin	SARS-CoV-2	Puerarin had good binding activity with ACE2 and hydrolase of SARS-CoV-2	[12]
16	Luteolin	SARS-CoV-2	Embrace satisfactory binding to ACE2, and also had good binding to core targets	[13-15]
17	β-Sitosterol	SARS-CoV-2
18	Formononetin	SARS-CoV-2
19	Icariine	SARS-CoV-2
20	Palmitic acid	SARS-CoV-2	These volatile oil components had good binding activity with ACE2	[16]
21	Linoleic acid	SARS-CoV-2
22	Anisic acid	SARS-CoV-2
23	Hesperidin	SARS-CoV-2	They had good affinity with the core target ACE2 of SARS-CoV-2	[17]
24	Naringin	SARS-CoV-2
25	Amygdalin	SARS-CoV-2
26	Liquiritin	SARS-CoV-2
27	Licoisoflavone	SARS-CoV-2
28	Curcumin	SARS-CoV-2	A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin as SARS-CoV-2 spike protein inhibitors	[18, 19]
29	Fortunellin	SARS-CoV-2	It could be well embedded into the active pocket of ACE2-SARS-CoV-2 S protein	[20]
30	Cannabigerolic acid	SARS-CoV-2	Prevent infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells	[21]
31	Tetrahydrocannabinolic acid	SARS-CoV-2
32	Cannabidiolic acid	SARS-CoV-2
33	1, 2, 3, 4, 6-Vegalacyl glucose	SARS-CoV-2	A safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors	[22]
34	Gingerol	SARS-CoV-2	Inhibited the viral protein of both wild-type and mutated S-protein of SARS-CoV-2	[23]
35	Thymol	SARS-CoV-2
36	Thymohydroquinone	SARS-CoV-2
37	Cyclocurcumin	SARS-CoV-2
38	Epigallocatechin gallate	SARS-CoV-2	The inhibitor blocked binding to S-protein in a dose-dependent manner	[24]
39	Quinoline-2-carboxylic acids	SARS-CoV-2	Blocked the interaction between SARS-CoV-2 RBD and ACE2 in a dose-dependent manner	[25]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Artemisinin

SARS-CoV-2

Artemisinin derivatives in preventing the interaction between the virus' SProtein and hACE2 receptor via selectively interacting with the Lys353 binding hotspot of SProtein

[4]

Rhein

SARS-CoV-2

Exhibited high inhibitory effect on ACE2

[5]

Forsythoside A

SARS-CoV-2

Withaferin A

SARS-CoV-2

Significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells

[6]

Piperine

SARS-CoV-2

Mangiferin

SARS-CoV-2

Thebaine

SARS-CoV-2

Berberine

SARS-CoV-2

Andrographolide

SARS-CoV-2

Nimbin

SARS-CoV-2

Salvianolic acid

SARS-CoV-2

Salvianolic acid C potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein

[7]

Quercetin

IAV

Quercetin showed interaction with the HA2 subunit

[8]

18β-Glycyrrhetinic acid

HRSV

Decreased HRSV infection largely by inhibiting viral attachment, internalization, and by stimulating IFN secretion

[10]

Chlorogenic acid

SARS-CoV-2

Chlorogenic acid could stably combine with Gln325 and Gln42/Asp38 in ACE2, respectively, which hindered the combination between S-protein and ACE2

[11]

Puerarin

SARS-CoV-2

Puerarin had good binding activity with ACE2 and hydrolase of SARS-CoV-2

[12]

Luteolin

SARS-CoV-2

Embrace satisfactory binding to ACE2, and also had good binding to core targets

[13-15]

β-Sitosterol

SARS-CoV-2

Formononetin

SARS-CoV-2

Icariine

SARS-CoV-2

Palmitic acid

SARS-CoV-2

These volatile oil components had good binding activity with ACE2

[16]

Linoleic acid

SARS-CoV-2

Anisic acid

SARS-CoV-2

Hesperidin

SARS-CoV-2

They had good affinity with the core target ACE2 of SARS-CoV-2

[17]

Naringin

SARS-CoV-2

Amygdalin

SARS-CoV-2

Liquiritin

SARS-CoV-2

Licoisoflavone

SARS-CoV-2

Curcumin

SARS-CoV-2

A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin as SARS-CoV-2 spike protein inhibitors

[18, 19]

Fortunellin

SARS-CoV-2

It could be well embedded into the active pocket of ACE2-SARS-CoV-2 S protein

[20]

Cannabigerolic acid

SARS-CoV-2

Prevent infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells

[21]

Tetrahydrocannabinolic acid

SARS-CoV-2

Cannabidiolic acid

SARS-CoV-2

1, 2, 3, 4, 6-Vegalacyl glucose

SARS-CoV-2

A safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors

[22]

Gingerol

SARS-CoV-2

Inhibited the viral protein of both wild-type and mutated S-protein of SARS-CoV-2

[23]

Thymol

SARS-CoV-2

Thymohydroquinone

SARS-CoV-2

Cyclocurcumin

SARS-CoV-2

Epigallocatechin gallate

SARS-CoV-2

The inhibitor blocked binding to S-protein in a dose-dependent manner

[24]

Quinoline-2-carboxylic acids

SARS-CoV-2

Blocked the interaction between SARS-CoV-2 RBD and ACE2 in a dose-dependent manner

[25]

No.	Compound	Antiviral species	Mechanism of action	Ref.
40	Luteolin	SARS-CoV-2	Embrace satisfactory binding to 3CL^pro, and also had good binding to core targets	[13, 14]
41	β-Sitosterol	SARS-CoV-2
42	Formononetin	SARS-CoV-2
43	Anhydroicaritin	SARS-CoV-2
44	Shinpterocarpin	SARS-CoV-2
45	Hederagenin	SARS-CoV-2	They had good affinity with the core target 3CL^pro of SARS-CoV-2	[17]
46	Jaranol	SARS-CoV-2
47	Linarin	SARS-CoV-2	It had strong binding with 3CL^pro	[20]
48	DL-Sulforaphane	SARS-CoV-2	SFN inhibits 3CL^pro in a reversible, mixed-type manner. SFN is a slow-binding inhibitor, following a two-step interaction an complex forms by specific binding of SFN to the active pocket of 3CL^pro, stabilizing the SFN-3CL^pro complex	[27]
49	Myricetin	SARS-CoV-2	Myricetin is an efficient covalent binder of the SARS-CoV-2 3CL^pro	[28]
50	Oridonin	SARS-CoV-2	Oridonin not only effectively inhibited SARS-CoV-2 3CL^pro activity, but also had some inhibitory effects on PL^pro	[29]
51	Prim-O-glucosylcimifugin	SARS-CoV-2	They had strong 3CL^pro inhibitory activities	[30]
52	Rosmarinic acid	SARS-CoV-2
53	Neohesperidin	SARS-CoV-2
54	Osthole	SARS-CoV-2
55	Licoisoflavone A	SARS-CoV-2	Exhibited significant inhibitions against RdRp	[31]
56	Vitisin B	H1N1	Suppresses H1N1 viral replication in MDCK and A549 cells	[33]
57	Quercetin	SARS-CoV-2	Quercetin could be shown to interact with 3CL^pro using biophysical techniques and bind to the active site in molecular simulations	[35, 36]
58	Andrographolide	SARS-CoV-2	Andrographolide was docked successfully in the binding site of SARS-CoV-2 3CL^pro	[37]
59	Chebulagic acid	SARS-CoV-2	By binding to SARS-CoV-2 3CL^pro at a pocket other that substrate binding site, chebulagic acid and punicalagin act as allosteric inhibitors in reversible, noncompetitive manner	[38]
60	Punicalagin	SARS-CoV-2
61	Scutellarein	SARS-CoV-2	Scutellarein was characterized as a potent 3CL^pro inhibitor	[39]
62	4-(2-Hydroxyethyl)phenol	SARS-CoV-2	Inhibit PL^pro by binding at an allosteric S2 site, an interaction and binding region for the Interferon-stimulated gene 15 molecule	[40]
63	4-Hydroxybenzaldehyde	SARS-CoV-2
64	Methyl 3, 4-dihydroxybenzoate	SARS-CoV-2

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Luteolin

SARS-CoV-2

Embrace satisfactory binding to 3CL^pro, and also had good binding to core targets

[13, 14]

β-Sitosterol

SARS-CoV-2

Formononetin

SARS-CoV-2

Anhydroicaritin

SARS-CoV-2

Shinpterocarpin

SARS-CoV-2

Hederagenin

SARS-CoV-2

They had good affinity with the core target 3CL^pro of SARS-CoV-2

[17]

Jaranol

SARS-CoV-2

Linarin

SARS-CoV-2

It had strong binding with 3CL^pro

[20]

DL-Sulforaphane

SARS-CoV-2

SFN inhibits 3CL^pro in a reversible, mixed-type manner. SFN is a slow-binding inhibitor, following a two-step interaction an complex forms by specific binding of SFN to the active pocket of 3CL^pro, stabilizing the SFN-3CL^pro complex

[27]

Myricetin

SARS-CoV-2

Myricetin is an efficient covalent binder of the SARS-CoV-2 3CL^pro

[28]

Oridonin

SARS-CoV-2

Oridonin not only effectively inhibited SARS-CoV-2 3CL^pro activity, but also had some inhibitory effects on PL^pro

[29]

Prim-O-glucosylcimifugin

SARS-CoV-2

They had strong 3CL^pro inhibitory activities

[30]

Rosmarinic acid

SARS-CoV-2

Neohesperidin

SARS-CoV-2

Osthole

SARS-CoV-2

Licoisoflavone A

SARS-CoV-2

Exhibited significant inhibitions against RdRp

[31]

Vitisin B

H1N1

Suppresses H1N1 viral replication in MDCK and A549 cells

[33]

Quercetin

SARS-CoV-2

Quercetin could be shown to interact with 3CL^pro using biophysical techniques and bind to the active site in molecular simulations

[35, 36]

Andrographolide

SARS-CoV-2

Andrographolide was docked successfully in the binding site of SARS-CoV-2 3CL^pro

[37]

Chebulagic acid

SARS-CoV-2

By binding to SARS-CoV-2 3CL^pro at a pocket other that substrate binding site, chebulagic acid and punicalagin act as allosteric inhibitors in reversible, noncompetitive manner

[38]

Punicalagin

SARS-CoV-2

Scutellarein

SARS-CoV-2

Scutellarein was characterized as a potent 3CL^pro inhibitor

[39]

4-(2-Hydroxyethyl)phenol

SARS-CoV-2

Inhibit PL^pro by binding at an allosteric S2 site, an interaction and binding region for the Interferon-stimulated gene 15 molecule

[40]

4-Hydroxybenzaldehyde

SARS-CoV-2

Methyl 3, 4-dihydroxybenzoate

SARS-CoV-2

No.	Compound	Antiviral species	Mechanism of action	Ref.
40	Luteolin	SARS-CoV-2	Embrace satisfactory binding to 3CL^pro, and also had good binding to core targets	[13, 14]
41	β-Sitosterol	SARS-CoV-2
42	Formononetin	SARS-CoV-2
43	Anhydroicaritin	SARS-CoV-2
44	Shinpterocarpin	SARS-CoV-2
45	Hederagenin	SARS-CoV-2	They had good affinity with the core target 3CL^pro of SARS-CoV-2	[17]
46	Jaranol	SARS-CoV-2
47	Linarin	SARS-CoV-2	It had strong binding with 3CL^pro	[20]
48	DL-Sulforaphane	SARS-CoV-2	SFN inhibits 3CL^pro in a reversible, mixed-type manner. SFN is a slow-binding inhibitor, following a two-step interaction an complex forms by specific binding of SFN to the active pocket of 3CL^pro, stabilizing the SFN-3CL^pro complex	[27]
49	Myricetin	SARS-CoV-2	Myricetin is an efficient covalent binder of the SARS-CoV-2 3CL^pro	[28]
50	Oridonin	SARS-CoV-2	Oridonin not only effectively inhibited SARS-CoV-2 3CL^pro activity, but also had some inhibitory effects on PL^pro	[29]
51	Prim-O-glucosylcimifugin	SARS-CoV-2	They had strong 3CL^pro inhibitory activities	[30]
52	Rosmarinic acid	SARS-CoV-2
53	Neohesperidin	SARS-CoV-2
54	Osthole	SARS-CoV-2
55	Licoisoflavone A	SARS-CoV-2	Exhibited significant inhibitions against RdRp	[31]
56	Vitisin B	H1N1	Suppresses H1N1 viral replication in MDCK and A549 cells	[33]
57	Quercetin	SARS-CoV-2	Quercetin could be shown to interact with 3CL^pro using biophysical techniques and bind to the active site in molecular simulations	[35, 36]
58	Andrographolide	SARS-CoV-2	Andrographolide was docked successfully in the binding site of SARS-CoV-2 3CL^pro	[37]
59	Chebulagic acid	SARS-CoV-2	By binding to SARS-CoV-2 3CL^pro at a pocket other that substrate binding site, chebulagic acid and punicalagin act as allosteric inhibitors in reversible, noncompetitive manner	[38]
60	Punicalagin	SARS-CoV-2
61	Scutellarein	SARS-CoV-2	Scutellarein was characterized as a potent 3CL^pro inhibitor	[39]
62	4-(2-Hydroxyethyl)phenol	SARS-CoV-2	Inhibit PL^pro by binding at an allosteric S2 site, an interaction and binding region for the Interferon-stimulated gene 15 molecule	[40]
63	4-Hydroxybenzaldehyde	SARS-CoV-2
64	Methyl 3, 4-dihydroxybenzoate	SARS-CoV-2

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Luteolin

SARS-CoV-2

Embrace satisfactory binding to 3CL^pro, and also had good binding to core targets

[13, 14]

β-Sitosterol

SARS-CoV-2

Formononetin

SARS-CoV-2

Anhydroicaritin

SARS-CoV-2

Shinpterocarpin

SARS-CoV-2

Hederagenin

SARS-CoV-2

They had good affinity with the core target 3CL^pro of SARS-CoV-2

[17]

Jaranol

SARS-CoV-2

Linarin

SARS-CoV-2

It had strong binding with 3CL^pro

[20]

DL-Sulforaphane

SARS-CoV-2

[27]

Myricetin

SARS-CoV-2

Myricetin is an efficient covalent binder of the SARS-CoV-2 3CL^pro

[28]

Oridonin

SARS-CoV-2

Oridonin not only effectively inhibited SARS-CoV-2 3CL^pro activity, but also had some inhibitory effects on PL^pro

[29]

Prim-O-glucosylcimifugin

SARS-CoV-2

They had strong 3CL^pro inhibitory activities

[30]

Rosmarinic acid

SARS-CoV-2

Neohesperidin

SARS-CoV-2

Osthole

SARS-CoV-2

Licoisoflavone A

SARS-CoV-2

Exhibited significant inhibitions against RdRp

[31]

Vitisin B

H1N1

Suppresses H1N1 viral replication in MDCK and A549 cells

[33]

Quercetin

SARS-CoV-2

Quercetin could be shown to interact with 3CL^pro using biophysical techniques and bind to the active site in molecular simulations

[35, 36]

Andrographolide

SARS-CoV-2

Andrographolide was docked successfully in the binding site of SARS-CoV-2 3CL^pro

[37]

Chebulagic acid

SARS-CoV-2

By binding to SARS-CoV-2 3CL^pro at a pocket other that substrate binding site, chebulagic acid and punicalagin act as allosteric inhibitors in reversible, noncompetitive manner

[38]

Punicalagin

SARS-CoV-2

Scutellarein

SARS-CoV-2

Scutellarein was characterized as a potent 3CL^pro inhibitor

[39]

4-(2-Hydroxyethyl)phenol

SARS-CoV-2

Inhibit PL^pro by binding at an allosteric S2 site, an interaction and binding region for the Interferon-stimulated gene 15 molecule

[40]

4-Hydroxybenzaldehyde

SARS-CoV-2

Methyl 3, 4-dihydroxybenzoate

SARS-CoV-2

No.	Compound	Antiviral species	Mechanism of action	Ref.
65	Punicalagin	IAV	Punicalgin blocks viral release from the infected cells by inhibiting NA activity	[44]
66	Chebulinic acid	IAV	Exert their inhibitory effect on the NA-mediated viral release	[45]
67	Chebulagic acid	IAV
68	Baicalein	H5N1	Baicalein interfered with the viral NA activity	[46]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Punicalagin

IAV

Punicalgin blocks viral release from the infected cells by inhibiting NA activity

[44]

Chebulinic acid

IAV

Exert their inhibitory effect on the NA-mediated viral release

[45]

Chebulagic acid

IAV

Baicalein

H5N1

Baicalein interfered with the viral NA activity

[46]

No.	Compound	Antiviral species	Mechanism of action	Ref.
65	Punicalagin	IAV	Punicalgin blocks viral release from the infected cells by inhibiting NA activity	[44]
66	Chebulinic acid	IAV	Exert their inhibitory effect on the NA-mediated viral release	[45]
67	Chebulagic acid	IAV
68	Baicalein	H5N1	Baicalein interfered with the viral NA activity	[46]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Punicalagin

IAV

Punicalgin blocks viral release from the infected cells by inhibiting NA activity

[44]

Chebulinic acid

IAV

Exert their inhibitory effect on the NA-mediated viral release

[45]

Chebulagic acid

IAV

Baicalein

H5N1

Baicalein interfered with the viral NA activity

[46]

No.	Compound	Antiviral species	Mechanism of action	Ref.
69	Epigoitrin	H1N1	Epigoitrin reduced the protein expression of MFN2, which elevated MAVS protein expression and subsequently increased the production of IFN-β and interferon inducible IFITM3	[50]
70	Baicalin	H1N1	Directly induce IFN-γ production in human CD4⁺ and CD8⁺ T cells and NK cells, and activate JAK/STAT-1 signaling pathway	[51]
RSV	The IFN-α and IFN-β in the BALB/c mouse infected by RSV could be evaluated significantly by baicalin	[52]
RSV	The expression of I-IFN in RSV infection rats could be down-regulated by baicalin. The expression of SOCS1/3 might be inhibited by reducing the expression IL-6 and IL-12 by baicalin	[53]
IAV	Baicalin exerts its anti-IVA effect by downregulating miR-146a to subsequently facilitate the type I IFN response	[54]
71	Baicalein	SARS-CoV-2	Baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum	[55]
72	Forsythoside	H1N1	TBK1, IRF3, MAPKp38, and NF-κB p65 in the forsythoside E-treated group were significantly downregulated	[56]
73	Phyllyrin	SARS-CoV-2	Regulation of NF-κB and MAPK signaling pathway and ERK pathways to improve immunity	[17, 57, 58]
74	Cirsimaritin	IAV	Suppress the activation of JNK MAPK and P38 MAPK in vitro, the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-8, and IL-10) and the inflammation-related protein COX-2 were downregulated	[59]
75	Polydatin	SARS-CoV-2	Inhibit macrophage activation in vitro	[60]
76	Isoliquiritin	SARS-CoV-2
77	Ephedrine	SARS-CoV-2
78	Atractylenolide III	SARS-CoV-2
79	Quercetin	RSV	Decreased the levels of TNF-α, IL-6, and IL-1α	[61]
SARS-CoV-2	Quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway	[63]
80	Resveratrol	RSV	Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression	[64]
81	Emodin	SARS-CoV-2	It had good binding ability with the core target of AKT1, IL-6, TP53, JUN, TNF	[65]
82	Lariciresinol-4-O-β-D-glucopyranoside	IAV	Inhibition of NF-κB pathway in influenza A virus-infected alveolar epithelial cells, decrease proinflammatory cytokine expression	[66]
83	Astaxanthin	SARS-CoV-2	Astaxanthin is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α	[67]
84	Watsonianone A	RSV	Watsonianone A inhibited NF-κB activation by suppressing IκBα phosphorylation	[68]
85	Luteolin	H1N1	Reduce the expression levels of the inflammatory cytokines TNF-α, IFN-γ, IL-1 and IL-10, thus reducing the pathological damage	[69]
86	Berbamine	H1N1	Induced activation of the type I interferon pathway	[70]
87	Carotene	SARS-CoV-2	Enter the active pocket of Akt1, prevent lung injury, lung fibrogenesis and virus infection	[71]
88	Kaempferol	SARS-CoV-2
89	Lonicerin	SARS-CoV-2	Inhibition of the arachidonic acid metabolism pathway and preventing the release of inflammatory factors can prevent the cytokine storm	[72]
90	Glycyrrhizic acid	SARS-CoV-2	Heightened release of proinflammatory cytokines IL-1β, IL-6 and IL-8 was attenuated by glycyrrhizin	[73]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Epigoitrin

H1N1

Epigoitrin reduced the protein expression of MFN2, which elevated MAVS protein expression and subsequently increased the production of IFN-β and interferon inducible IFITM3

[50]

Baicalin

H1N1

Directly induce IFN-γ production in human CD4⁺ and CD8⁺ T cells and NK cells, and activate JAK/STAT-1 signaling pathway

[51]

RSV

The IFN-α and IFN-β in the BALB/c mouse infected by RSV could be evaluated significantly by baicalin

[52]

RSV

The expression of I-IFN in RSV infection rats could be down-regulated by baicalin. The expression of SOCS1/3 might be inhibited by reducing the expression IL-6 and IL-12 by baicalin

[53]

IAV

Baicalin exerts its anti-IVA effect by downregulating miR-146a to subsequently facilitate the type I IFN response

[54]

Baicalein

SARS-CoV-2

Baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum

[55]

Forsythoside

H1N1

TBK1, IRF3, MAPKp38, and NF-κB p65 in the forsythoside E-treated group were significantly downregulated

[56]

Phyllyrin

SARS-CoV-2

Regulation of NF-κB and MAPK signaling pathway and ERK pathways to improve immunity

[17, 57, 58]

Cirsimaritin

IAV

Suppress the activation of JNK MAPK and P38 MAPK in vitro, the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-8, and IL-10) and the inflammation-related protein COX-2 were downregulated

[59]

Polydatin

SARS-CoV-2

Inhibit macrophage activation in vitro

[60]

Isoliquiritin

SARS-CoV-2

Ephedrine

SARS-CoV-2

Atractylenolide III

SARS-CoV-2

Quercetin

RSV

Decreased the levels of TNF-α, IL-6, and IL-1α

[61]

SARS-CoV-2

Quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway

[63]

Resveratrol

RSV

Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression

[64]

Emodin

SARS-CoV-2

It had good binding ability with the core target of AKT1, IL-6, TP53, JUN, TNF

[65]

Lariciresinol-4-O-β-D-glucopyranoside

IAV

Inhibition of NF-κB pathway in influenza A virus-infected alveolar epithelial cells, decrease proinflammatory cytokine expression

[66]

Astaxanthin

SARS-CoV-2

Astaxanthin is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α

[67]

Watsonianone A

RSV

Watsonianone A inhibited NF-κB activation by suppressing IκBα phosphorylation

[68]

Luteolin

H1N1

Reduce the expression levels of the inflammatory cytokines TNF-α, IFN-γ, IL-1 and IL-10, thus reducing the pathological damage

[69]

Berbamine

H1N1

Induced activation of the type I interferon pathway

[70]

Carotene

SARS-CoV-2

Enter the active pocket of Akt1, prevent lung injury, lung fibrogenesis and virus infection

[71]

Kaempferol

SARS-CoV-2

Lonicerin

SARS-CoV-2

Inhibition of the arachidonic acid metabolism pathway and preventing the release of inflammatory factors can prevent the cytokine storm

[72]

Glycyrrhizic acid

SARS-CoV-2

Heightened release of proinflammatory cytokines IL-1β, IL-6 and IL-8 was attenuated by glycyrrhizin

[73]

No.	Compound	Antiviral species	Mechanism of action	Ref.
69	Epigoitrin	H1N1	Epigoitrin reduced the protein expression of MFN2, which elevated MAVS protein expression and subsequently increased the production of IFN-β and interferon inducible IFITM3	[50]
70	Baicalin	H1N1	Directly induce IFN-γ production in human CD4⁺ and CD8⁺ T cells and NK cells, and activate JAK/STAT-1 signaling pathway	[51]
RSV	The IFN-α and IFN-β in the BALB/c mouse infected by RSV could be evaluated significantly by baicalin	[52]
RSV	The expression of I-IFN in RSV infection rats could be down-regulated by baicalin. The expression of SOCS1/3 might be inhibited by reducing the expression IL-6 and IL-12 by baicalin	[53]
IAV	Baicalin exerts its anti-IVA effect by downregulating miR-146a to subsequently facilitate the type I IFN response	[54]
71	Baicalein	SARS-CoV-2	Baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum	[55]
72	Forsythoside	H1N1	TBK1, IRF3, MAPKp38, and NF-κB p65 in the forsythoside E-treated group were significantly downregulated	[56]
73	Phyllyrin	SARS-CoV-2	Regulation of NF-κB and MAPK signaling pathway and ERK pathways to improve immunity	[17, 57, 58]
74	Cirsimaritin	IAV	Suppress the activation of JNK MAPK and P38 MAPK in vitro, the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-8, and IL-10) and the inflammation-related protein COX-2 were downregulated	[59]
75	Polydatin	SARS-CoV-2	Inhibit macrophage activation in vitro	[60]
76	Isoliquiritin	SARS-CoV-2
77	Ephedrine	SARS-CoV-2
78	Atractylenolide III	SARS-CoV-2
79	Quercetin	RSV	Decreased the levels of TNF-α, IL-6, and IL-1α	[61]
SARS-CoV-2	Quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway	[63]
80	Resveratrol	RSV	Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression	[64]
81	Emodin	SARS-CoV-2	It had good binding ability with the core target of AKT1, IL-6, TP53, JUN, TNF	[65]
82	Lariciresinol-4-O-β-D-glucopyranoside	IAV	Inhibition of NF-κB pathway in influenza A virus-infected alveolar epithelial cells, decrease proinflammatory cytokine expression	[66]
83	Astaxanthin	SARS-CoV-2	Astaxanthin is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α	[67]
84	Watsonianone A	RSV	Watsonianone A inhibited NF-κB activation by suppressing IκBα phosphorylation	[68]
85	Luteolin	H1N1	Reduce the expression levels of the inflammatory cytokines TNF-α, IFN-γ, IL-1 and IL-10, thus reducing the pathological damage	[69]
86	Berbamine	H1N1	Induced activation of the type I interferon pathway	[70]
87	Carotene	SARS-CoV-2	Enter the active pocket of Akt1, prevent lung injury, lung fibrogenesis and virus infection	[71]
88	Kaempferol	SARS-CoV-2
89	Lonicerin	SARS-CoV-2	Inhibition of the arachidonic acid metabolism pathway and preventing the release of inflammatory factors can prevent the cytokine storm	[72]
90	Glycyrrhizic acid	SARS-CoV-2	Heightened release of proinflammatory cytokines IL-1β, IL-6 and IL-8 was attenuated by glycyrrhizin	[73]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Epigoitrin

H1N1

Epigoitrin reduced the protein expression of MFN2, which elevated MAVS protein expression and subsequently increased the production of IFN-β and interferon inducible IFITM3

[50]

Baicalin

H1N1

Directly induce IFN-γ production in human CD4⁺ and CD8⁺ T cells and NK cells, and activate JAK/STAT-1 signaling pathway

[51]

RSV

The IFN-α and IFN-β in the BALB/c mouse infected by RSV could be evaluated significantly by baicalin

[52]

RSV

The expression of I-IFN in RSV infection rats could be down-regulated by baicalin. The expression of SOCS1/3 might be inhibited by reducing the expression IL-6 and IL-12 by baicalin

[53]

IAV

Baicalin exerts its anti-IVA effect by downregulating miR-146a to subsequently facilitate the type I IFN response

[54]

Baicalein

SARS-CoV-2

Baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum

[55]

Forsythoside

H1N1

TBK1, IRF3, MAPKp38, and NF-κB p65 in the forsythoside E-treated group were significantly downregulated

[56]

Phyllyrin

SARS-CoV-2

Regulation of NF-κB and MAPK signaling pathway and ERK pathways to improve immunity

[17, 57, 58]

Cirsimaritin

IAV

[59]

Polydatin

SARS-CoV-2

Inhibit macrophage activation in vitro

[60]

Isoliquiritin

SARS-CoV-2

Ephedrine

SARS-CoV-2

Atractylenolide III

SARS-CoV-2

Quercetin

RSV

Decreased the levels of TNF-α, IL-6, and IL-1α

[61]

SARS-CoV-2

Quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway

[63]

Resveratrol

RSV

Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression

[64]

Emodin

SARS-CoV-2

It had good binding ability with the core target of AKT1, IL-6, TP53, JUN, TNF

[65]

Lariciresinol-4-O-β-D-glucopyranoside

IAV

Inhibition of NF-κB pathway in influenza A virus-infected alveolar epithelial cells, decrease proinflammatory cytokine expression

[66]

Astaxanthin

SARS-CoV-2

Astaxanthin is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α

[67]

Watsonianone A

RSV

Watsonianone A inhibited NF-κB activation by suppressing IκBα phosphorylation

[68]

Luteolin

H1N1

Reduce the expression levels of the inflammatory cytokines TNF-α, IFN-γ, IL-1 and IL-10, thus reducing the pathological damage

[69]

Berbamine

H1N1

Induced activation of the type I interferon pathway

[70]

Carotene

SARS-CoV-2

Enter the active pocket of Akt1, prevent lung injury, lung fibrogenesis and virus infection

[71]

Kaempferol

SARS-CoV-2

Lonicerin

SARS-CoV-2

Inhibition of the arachidonic acid metabolism pathway and preventing the release of inflammatory factors can prevent the cytokine storm

[72]

Glycyrrhizic acid

SARS-CoV-2

Heightened release of proinflammatory cytokines IL-1β, IL-6 and IL-8 was attenuated by glycyrrhizin

[73]

天然药物抗呼吸道病毒活性成分及其作用机制研究进展

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王剑 ¹^,^*^,^# , 张萍萍 ¹^,^# , 于健 ¹^,^* , 王京龙 ¹ , 崔清华 ²

药学学报 | 综述 2024,59(4): 853-865

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药学学报 | 综述 2024, 59(4): 853-865

天然药物抗呼吸道病毒活性成分及其作用机制研究进展

全屏

王剑¹^,^*^,^#, 张萍萍¹^,^#, 于健¹^,^*, 王京龙¹, 崔清华²

作者信息

1.枣庄学院食品科学与制药工程学院, 山东枣庄 277160

2.山东中医药大学药学院, 山东济南 250355

通讯作者:

^*王剑, E-mail: hwangjian08@163.com;

于健, E-mail: 3179877749@qq.com

Progress of active ingredients of natural drugs and their mechanism of antiviral actions

Jian WANG¹^,^*, Ping-ping ZHANG¹, Jian YU¹^,^*, Jing-long WANG¹, Qing-hua CUI²

Affiliations

1. College of Food Science and Pharmaceutical Engineering, Zaozhuang University, Zaozhuang 277160, China

2. College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China

出版时间: 2024-04-12 doi: 10.16438/j.0513-4870.2023-0996

文章导航

摘要

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人类病毒性呼吸道疾病是一类广泛流行的传染性疾病, 呼吸道病毒感染的发病率在全球居民发病率总体结构中占据主要地位, 是导致人类急性和致死性疾病的主要病因之一。天然产物结构多样、作用机制新颖, 具有调节机体免疫与抗呼吸道病毒的作用, 在治疗呼吸道病毒疾病方面具有独特的优势。本文综合目前天然药物防治呼吸道病毒的研究进展, 以天然药物抗呼吸道病毒活性成分的作用机制进行分类, 以期为未来的呼吸道疾病的临床治疗与药物发现提供参考依据。

关键词

天然药物 / 活性成分 / 新型冠状病毒 / 呼吸道病毒感染 / 抗病毒作用机制

Abstract

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Human viral respiratory disease is a kind of widely prevalent infectious disease. The incidence rate of respiratory virus infection occupies a major position in the overall structure of global incidence rate of residents, and is one of the main causes of acute and fatal human diseases. Natural products have diverse structures and novel mechanisms of action, which can regulate body immunity and resist respiratory viruses, and have unique advantages in the treatment of respiratory viral diseases. This article summarizes the current research progress of natural drugs in the prevention and treatment of respiratory viruses, classifies the action mechanism of the active components of natural drugs against respiratory viruses, to provide reference basis for clinical treatment and drug discovery of respiratory diseases in the future.

Key words

natural drug / active ingredient / SARS-CoV-2 / respiratory virus infection / mechanism of antiviral action

引用本文

王剑, 张萍萍, 于健, 王京龙, 崔清华. 天然药物抗呼吸道病毒活性成分及其作用机制研究进展. 药学学报, 2024 , 59 (4) : 853 -865 . DOI: 10.16438/j.0513-4870.2023-0996

Jian WANG, Ping-ping ZHANG, Jian YU, Jing-long WANG, Qing-hua CUI. Progress of active ingredients of natural drugs and their mechanism of antiviral actions[J]. Acta Pharmaceutica Sinica, 2024 , 59 (4) : 853 -865 . DOI: 10.16438/j.0513-4870.2023-0996

正文

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呼吸道病毒以空气传播(呼吸道飞沫传播) 为主, 传染性较强, 极易引起大规模流行性疾病。新型冠状病毒肺炎(corona virus disease 2019, COVID-19) 疫情暴发以来, 传播迅速, 据WHO统计, 截至2023年8月17日, 全球累计确诊COVID-19病例超过7.69亿, 死亡人数逾695万^[1], 对全球社会经济造成冲击, 在全球引发了社会动乱并对人体产生不可忽视的后遗症。呼吸道病毒感染是导致人类急性和致死性疾病的主要病因之一, 是全球卫生安全的重要威胁, 现虽然已研发出针对原始株的疫苗, 但潜在变异株的威胁仍不容小觑。

目前抗呼吸道病毒药物以西药为主, 主要有洛匹那韦、金刚烷胺、金刚乙胺奥司他韦等, 但若使用不当会引起急性肾衰竭等不良反应。目前广泛使用的广谱抗病毒药物利巴韦林的药效仍存在争议, 其不良反应也令人担忧。鉴于上述现状, 开发高效、低毒、使用便捷的呼吸道病毒药物具有重要意义, 而从天然药物中筛选活性成分已经成为开发各类治疗药物的有效途径与手段。

Liu等^[2]从清金化痰汤的活性成分入手, 利用超高效液相色谱-四极杆飞行时间质谱(UPLC-Q-TOF/MS) 技术分析了其中的抗病毒天然药物活性成分的组成, 对甲型流感病毒(influenza A virus, IAV) 感染后的差异表达基因进行了RNA-seq筛选, 揭示了清金化痰汤治疗IAV肺炎的机制。天然药物活性成分抗病毒机制是什么？根据中医理论, 天然药物抗病毒主要有两种策略, 为“祛邪”和“扶正”。“祛邪”对应于直接抑制病毒的活性, “扶正”对应于宿主的免疫调节、炎症控制和预防病毒^[3]。天然药物是重要的药物开发资源, 与化学合成药物相比, 天然药物具有结构多样性、毒性低、作用机制新颖、能够调节机体免疫功能等优点, 因此从植物、微生物中寻找药物先导化合物具有极好的潜力。本文将近几年天然药物的活性成分进行归纳并阐明其抗呼吸道病毒的作用机制, 以期为未来的人类病毒性呼吸道疾病的临床治疗与药物发现提供一些有益的参考。

1 直接作用于病毒

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1.1 抑制病毒的吸附

血管紧张素转化酶2 (angiotensin-converting enzyme 2, ACE2) 是存在于宿主细胞上的一种受体, 新型冠状病毒表面的刺突蛋白可以协助病毒找到宿主细胞上的ACE2受体并诱导病毒与受体细胞相结合, 吸附宿主细胞, 在酶的反应下病毒的包膜与宿主细胞融合进而入侵宿主细胞。Sehailia等^[4]研究发现青蒿素及其衍生物可以缠绕新冠病毒刺突蛋白的Lys353和Lys31结合位点, 从而影响其与人体ACE2受体蛋白的融合, 从而阻止病毒吸附宿主细胞。Chen等^[5]使用高分辨质谱(high resolution mass spectrum, HRMS) 和非靶向数据挖掘方法的组合, 检测到连花清瘟中132种成分或衍生物, 通过ACE2生物色谱法筛选的数据, 确定了大黄酸、连翘苷A、连翘苷I、新绿原酸及其异构体对ACE2表现出高度抑制作用。Maurya等^[6]研究表明姜黄素、醉茄素A、胡椒碱、芒果苷、蒂巴因、小檗碱、穿心莲内酯和印楝素对SARS-CoV-2的刺突蛋白和ACE2受体均具有显著的结合亲和力, 可以阻断刺突蛋白与ACE2受体的结合抑制病毒吸附宿主细胞。Yang等^[7]发现中药丹参水溶性单体成分丹酚酸通过阻止刺突蛋白六螺旋束结构形成, 有效抑制新型冠状病毒的吸附。

流感病毒(influenza virus, IV) 表面的糖蛋白血凝素(HA) 与宿主细胞的唾液酸受体结合, 引起病毒包膜与宿主细胞膜融合, 病毒以胞吞的形式入侵宿主细胞。Wu等^[8]发现槲皮素可通过与流感病毒血凝素蛋白结合, 竞争性抑制流感病毒血凝素与宿主细胞的唾液酸结合, 抑制病毒包膜与宿主细胞膜融合, 抑制病毒以胞吞形式入侵宿主细胞。

人呼吸道合胞病毒(human respiratory syncytial virus, HRSV) 含有三种膜结合蛋白: 附着蛋白(G)、融合蛋白(F)、病毒孔蛋白(SH)。蛋白G可与宿主细胞结合, 蛋白F可以融合病毒和细胞膜, 使病毒核糖核蛋白能够到达细胞质。三种糖蛋白相互作用使病毒入侵宿主细胞^[9]。Yeh等^[10]研究发现甘草通过抑制病毒附着、内化减少HRSV感染。18β-甘草次酸可能是影响甘草抗HRSV活性的活性成分之一。通过抑制病毒吸附的抗呼吸道病毒的天然药物活性成分见表 1^{[4-8, 10-25]}。

1.2 抑制病毒的增殖

病毒感染特定的活细胞后, 可以在病毒核酸的控制下, 利用宿主细胞的能量系统、核糖体等合成病毒核酸和蛋白质, 最后组装成结构完整、具有感染力的成熟病毒颗粒。冠状病毒3C样蛋白酶(3C-like protease, 3CL^pro) 与木瓜蛋白酶样蛋白酶(papain-like protease, PL^pro) 在病毒增殖过程能够将多肽链切割分解成病毒复制需要的片段^[26]。通过研究发现, 木犀草素、β-谷甾醇、芒柄花黄素、紫檀素、蒙花苷、金丝桃苷等通过与3CL^pro特异性结合, 阻止3CL^pro发挥作用^{[13, 14, 17, 20]}。Chen等^[27]研究发现萝卜硫素(SFN) 是一种缓慢结合的抑制剂, SFN与3CL^pro能够发生共价反应, 形成了SFN-3CL^pro复合物, 从而阻断3CL^pro的作用。Su等^[28]研究发现杨梅素可以与3CL^pro共价结合, 阻止3CL^pro发挥作用, 从而抑制病毒的增殖; Zhang等^[29]研究发现冬凌草甲素不仅能够抑制3CL^pro的活性, 而且在高浓度下可以阻止PL^pro主导的反应活动, 从而阻止病毒的增殖。新橙皮苷、蛇床子素等与PL^pro结合, 阻止PL^pro发挥作用, 从而抑制病毒增殖^[30]。Xu等^[31]研究发现西北甘草异黄酮和甘草异黄酮A可以与RNA依赖的RNA聚合酶(RNA-dependent RNA polymerase, RdRp) 结合形成复合物, 阻止RdRp发挥作用, 从而抑制病毒的增殖。

核因子-κB (nuclear factor-κB, NF-κB) 信号通路可以调节流感病毒RNA合成, 在病毒的复制过程中发挥重要作用^[32]。葡萄红素B能够抑制H1N1病毒在MDCK和A549细胞中的复制, 并通过IκB激酶(IκB kinase, IKK) 去磷酸化抑制NF-κB转入细胞核, 从而降低了病毒诱导的活性氧(reactive oxygen species, ROS) 的生成^[33]。细胞周期蛋白依赖性激酶抑制剂p21可以直接与病毒聚合酶酸性蛋白结合, 并通过破坏核糖核蛋白复合物的形成来限制IAV聚合酶活性, 从而阻止病毒增殖^[34]。通过抑制病毒增殖抗呼吸道病毒的天然药物活性成分见表 2^{[13, 14, 17, 20, 27-31, 33, 35-40]}。

1.3 阻止病毒释放

在流感病毒中, 神经氨酸酶(NA)、血凝素(HA) 和病毒M2蛋白被输出到质膜上, 与病毒核糖核蛋白(viral ribonucleoprotein, vRNP) 组装产生子代IAV粒子。在NA催化下, 新组装的病毒从宿主细胞释放传播^[41-43]。NA是流感病毒中重要的包膜糖蛋白之一, 在成熟的病毒细胞从宿主细胞分离时, 病毒表面的血凝素通过唾液酸与宿主细胞相连, 神经氨酸酶具有水解唾液酸的功能, 使病毒繁殖释放。Li等^[44]研究发现安石榴苷抑制流感病毒的神经氨酸酶, 阻止唾液酸的分解, 阻断病毒释放。诃子酸和诃子林鞣酸可以抑制病毒NA蛋白的活性, 破坏病毒与宿主细胞上唾液酸的结合, 在感染的细胞中阻止病毒释放^[45]。通过阻止病毒释放抗呼吸道病毒的天然药物活性成分见表 3^[44-46]。

2 免疫调节

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在病毒感染后, 细胞通过释放细胞因子、趋化因子等信号, 激活巨噬细胞、自然杀伤细胞(NK) 和其他免疫细胞, 以杀死和消除被感染的细胞。一旦调节失去平衡, 就会导致过度的免疫反应和组织损伤^[47]。研究表明, 细胞周期蛋白依赖性激酶抑制剂p21可以直接调节巨噬细胞分化和活性来调节免疫反应^[48]。

干扰素(interferon, IFN) 是一种广谱抗病毒糖蛋白, 作为免疫系统的触发、调节和效应器, 参与病毒感染的许多生理反应, 是最重要的细胞因子^[49]。Luo等^[50]研究发现表告依春降低了线粒体融合蛋白2 (mitofusin 2, MFN2) 的表达, 从而提高了线粒体抗病毒信号蛋白(mitochondrial antiviral signaling protein, MAVS)的表达, 进而增加了干扰素β (IFN-β) 和干扰素诱导的跨膜蛋白3 (interferon-induced transmembrane protein 3, IFITM3) 的产生。研究发现黄芩苷能明显增加呼吸道合胞病毒(respiratory syncytial virus, RSV) 感染小鼠的干扰素α (IFN-α)、IFN-β及干扰素γ (IFN-γ) 的表达来发挥抗RSV的作用^{[51, 52]}。连翘苷E、连翘苷、马鞭草苷和大黄素, 通过调节1型IFN、NF-κB与丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) 等信号通路, 改善病毒感染小鼠的症状^[53-56]。

天然活性成分还可以通过调节炎症因子的释放, 来避免炎症风暴。大量研究发现连翘苷E、连翘苷、马鞭草苷、大黄素、橙皮苷与新绿原酸等可以调节免疫反应控制细胞因子的释放, 抑制炎症与细胞因子风暴, 改善细胞机体免疫调节的失衡^{[17, 57, 58]}。蓟黄素可以通过体外抑制JNK MAPK和P38 MAPK的激活, 下调促炎细胞因子肿瘤坏死因子-α (TNF-α)、白细胞介素1β (IL-1β)、白细胞介素-8 (IL-8) 和白细胞介素-10 (IL-10) 和炎症相关蛋白环氧化酶2 (cyclooxygenase 2, COX-2) 的表达水平从而有效治愈IAV感染^[59]。Xu等^[31]研究发现甘草查尔酮B、西北甘草异黄酮和刺甘草查尔酮具有较好抗炎活性抑制严重急性呼吸综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) 所致炎症因子的释放, 且与剂量有依赖性。Zhao等^[60]研究发现虎杖苷、异甘草苷、麻黄碱、山柰酚、苍术内酯I和毛蕊花苷等成分可以抑制巨噬细胞的活化, 减轻炎症症状。研究发现, 槲皮素、木犀草素和芹菜素等核心成分靶向与白细胞介素-6 (IL-6) 结合下调IL-6的水平, 能有效阻断炎症风暴^[61]。谷氨酰胺酶抑制剂JHU-083通过调节l-谷氨酰胺代谢, 从而缓解病毒刺激诱导的铁死亡, 减轻炎症的严重程度, 减轻H1N1病毒对机体的损伤^[62]。通过免疫调节抗呼吸道病毒的天然药物活性成分见表 4^{[17, 50-61, 63-73]}。

3 小结与展望

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SARS-CoV-2大流行给全人类带来了严重危害, 新冠病毒反复感染仍在持续, 如何有效减轻相关疾病负担是当下的重要课题。研究发现, 新冠病毒表现出明显的免疫学逃逸和解剖学逃逸特征^[74]: 一方面, 层出不穷的变异株可以逃逸既往自然感染或疫苗诱导产生的保护性抗体; 另一方面, 人体上呼吸道的抗体水平比外周血中的抗体水平低数百倍^[75], 导致新冠病毒在感染和复制的第一站, 即鼻腔中发生解剖学逃逸。因此, 新冠病毒、流感病毒等非系统性感染类呼吸道病毒易反复感染。呼吸道病毒对公众健康和经济稳定构成持续威胁, 为传统抗病毒药物的研发带来巨大挑战。

天然产物结构丰富多变, 很多分子具有很好的药理活性。大量研究表明, 自然界中的天然药物含有大量活性物质具有调节机体免疫与抗呼吸道病毒的作用, 随着研究的深入开展, 天然药物及其活性物质在作为抵抗呼吸道病毒侵害、促进人体免疫和治疗疾病的候选药物方面展现出良好的应用前景。近几年来, 研究人员不仅从微生物、植物及海洋生物中分离出许多具有生理活性且结构新颖的天然化合物, 也发现了一些已知化合物具有较好的抗呼吸道病毒活性, 且更深入地开展了构效关系的研究, 为这些天然产物用作抗呼吸道病毒药物的相关研究提供了更多的参考信息。

病毒带来的危害让人们意识到开发抗病毒药物和治疗方案的迫切需求, 目前的抗病毒策略集中于抗体、疫苗、小分子药物等传统技术手段, 而RNA包膜病毒的高频突变特性往往会促使原有技术方法的失效。研究发现, 针对亚细胞结构稳态可能是一种有前途的抗病毒策略^[76]。天然药物在抗呼吸道病毒中有很大潜力, 其相关作用机制仍需研究者们继续探索。

作者贡献: 王剑和张萍萍负责文献检索及论文撰写; 王京龙和崔清华负责相关资料的收集和文章选题; 王剑、张萍萍和于健负责文章的修改和校对文章。

利益冲突: 作者声明无利益冲突。

基金

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国家科技重大项目(2018ZX09101003)
山东省重点研发计划项目(2022TZXD0019)
枣庄学院博士科研启动基金项目(21/1020712)

参考文献

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文献

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2024年第59卷第4期

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doi: 10.16438/j.0513-4870.2023-0996

接收时间：2023-08-24
首发时间：2025-11-28
出版时间：2024-04-12

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收稿日期：2023-08-24
修回日期：2023-11-06

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国家科技重大项目(2018ZX09101003)

山东省重点研发计划项目(2022TZXD0019)

枣庄学院博士科研启动基金项目(21/1020712)

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1.枣庄学院食品科学与制药工程学院, 山东枣庄 277160

2.山东中医药大学药学院, 山东济南 250355

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^*王剑, E-mail: hwangjian08@163.com;

于健, E-mail: 3179877749@qq.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

No.	Compound	Antiviral species	Mechanism of action	Ref.
1	Artemisinin	SARS-CoV-2	Artemisinin derivatives in preventing the interaction between the virus' SProtein and hACE2 receptor via selectively interacting with the Lys353 binding hotspot of SProtein	[4]
2	Rhein	SARS-CoV-2	Exhibited high inhibitory effect on ACE2	[5]
3	Forsythoside A	SARS-CoV-2
4	Withaferin A	SARS-CoV-2	Significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells	[6]
5	Piperine	SARS-CoV-2
6	Mangiferin	SARS-CoV-2
7	Thebaine	SARS-CoV-2
8	Berberine	SARS-CoV-2
9	Andrographolide	SARS-CoV-2
10	Nimbin	SARS-CoV-2
11	Salvianolic acid	SARS-CoV-2	Salvianolic acid C potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein	[7]
12	Quercetin	IAV	Quercetin showed interaction with the HA2 subunit	[8]
13	18β-Glycyrrhetinic acid	HRSV	Decreased HRSV infection largely by inhibiting viral attachment, internalization, and by stimulating IFN secretion	[10]
14	Chlorogenic acid	SARS-CoV-2	Chlorogenic acid could stably combine with Gln325 and Gln42/Asp38 in ACE2, respectively, which hindered the combination between S-protein and ACE2	[11]
15	Puerarin	SARS-CoV-2	Puerarin had good binding activity with ACE2 and hydrolase of SARS-CoV-2	[12]
16	Luteolin	SARS-CoV-2	Embrace satisfactory binding to ACE2, and also had good binding to core targets	[13-15]
17	β-Sitosterol	SARS-CoV-2
18	Formononetin	SARS-CoV-2
19	Icariine	SARS-CoV-2
20	Palmitic acid	SARS-CoV-2	These volatile oil components had good binding activity with ACE2	[16]
21	Linoleic acid	SARS-CoV-2
22	Anisic acid	SARS-CoV-2
23	Hesperidin	SARS-CoV-2	They had good affinity with the core target ACE2 of SARS-CoV-2	[17]
24	Naringin	SARS-CoV-2
25	Amygdalin	SARS-CoV-2
26	Liquiritin	SARS-CoV-2
27	Licoisoflavone	SARS-CoV-2
28	Curcumin	SARS-CoV-2	A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin as SARS-CoV-2 spike protein inhibitors	[18, 19]
29	Fortunellin	SARS-CoV-2	It could be well embedded into the active pocket of ACE2-SARS-CoV-2 S protein	[20]
30	Cannabigerolic acid	SARS-CoV-2	Prevent infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells	[21]
31	Tetrahydrocannabinolic acid	SARS-CoV-2
32	Cannabidiolic acid	SARS-CoV-2
33	1, 2, 3, 4, 6-Vegalacyl glucose	SARS-CoV-2	A safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors	[22]
34	Gingerol	SARS-CoV-2	Inhibited the viral protein of both wild-type and mutated S-protein of SARS-CoV-2	[23]
35	Thymol	SARS-CoV-2
36	Thymohydroquinone	SARS-CoV-2
37	Cyclocurcumin	SARS-CoV-2
38	Epigallocatechin gallate	SARS-CoV-2	The inhibitor blocked binding to S-protein in a dose-dependent manner	[24]
39	Quinoline-2-carboxylic acids	SARS-CoV-2	Blocked the interaction between SARS-CoV-2 RBD and ACE2 in a dose-dependent manner	[25]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Artemisinin

SARS-CoV-2

Artemisinin derivatives in preventing the interaction between the virus' SProtein and hACE2 receptor via selectively interacting with the Lys353 binding hotspot of SProtein

[4]

Rhein

SARS-CoV-2

Exhibited high inhibitory effect on ACE2

[5]

Forsythoside A

SARS-CoV-2

Withaferin A

SARS-CoV-2

Significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells

[6]

Piperine

SARS-CoV-2

Mangiferin

SARS-CoV-2

Thebaine

SARS-CoV-2

Berberine

SARS-CoV-2

Andrographolide

SARS-CoV-2

Nimbin

SARS-CoV-2

Salvianolic acid

SARS-CoV-2

Salvianolic acid C potently inhibit SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein

[7]

Quercetin

IAV

Quercetin showed interaction with the HA2 subunit

[8]

18β-Glycyrrhetinic acid

HRSV

Decreased HRSV infection largely by inhibiting viral attachment, internalization, and by stimulating IFN secretion

[10]

Chlorogenic acid

SARS-CoV-2

Chlorogenic acid could stably combine with Gln325 and Gln42/Asp38 in ACE2, respectively, which hindered the combination between S-protein and ACE2

[11]

Puerarin

SARS-CoV-2

Puerarin had good binding activity with ACE2 and hydrolase of SARS-CoV-2

[12]

Luteolin

SARS-CoV-2

Embrace satisfactory binding to ACE2, and also had good binding to core targets

[13-15]

β-Sitosterol

SARS-CoV-2

Formononetin

SARS-CoV-2

Icariine

SARS-CoV-2

Palmitic acid

SARS-CoV-2

These volatile oil components had good binding activity with ACE2

[16]

Linoleic acid

SARS-CoV-2

Anisic acid

SARS-CoV-2

Hesperidin

SARS-CoV-2

They had good affinity with the core target ACE2 of SARS-CoV-2

[17]

Naringin

SARS-CoV-2

Amygdalin

SARS-CoV-2

Liquiritin

SARS-CoV-2

Licoisoflavone

SARS-CoV-2

Curcumin

SARS-CoV-2

A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin as SARS-CoV-2 spike protein inhibitors

[18, 19]

Fortunellin

SARS-CoV-2

It could be well embedded into the active pocket of ACE2-SARS-CoV-2 S protein

[20]

Cannabigerolic acid

SARS-CoV-2

Prevent infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells

[21]

Tetrahydrocannabinolic acid

SARS-CoV-2

Cannabidiolic acid

SARS-CoV-2

1, 2, 3, 4, 6-Vegalacyl glucose

SARS-CoV-2

A safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors

[22]

Gingerol

SARS-CoV-2

Inhibited the viral protein of both wild-type and mutated S-protein of SARS-CoV-2

[23]

Thymol

SARS-CoV-2

Thymohydroquinone

SARS-CoV-2

Cyclocurcumin

SARS-CoV-2

Epigallocatechin gallate

SARS-CoV-2

The inhibitor blocked binding to S-protein in a dose-dependent manner

[24]

Quinoline-2-carboxylic acids

SARS-CoV-2

Blocked the interaction between SARS-CoV-2 RBD and ACE2 in a dose-dependent manner

[25]

No.	Compound	Antiviral species	Mechanism of action	Ref.
40	Luteolin	SARS-CoV-2	Embrace satisfactory binding to 3CL^pro, and also had good binding to core targets	[13, 14]
41	β-Sitosterol	SARS-CoV-2
42	Formononetin	SARS-CoV-2
43	Anhydroicaritin	SARS-CoV-2
44	Shinpterocarpin	SARS-CoV-2
45	Hederagenin	SARS-CoV-2	They had good affinity with the core target 3CL^pro of SARS-CoV-2	[17]
46	Jaranol	SARS-CoV-2
47	Linarin	SARS-CoV-2	It had strong binding with 3CL^pro	[20]
48	DL-Sulforaphane	SARS-CoV-2	SFN inhibits 3CL^pro in a reversible, mixed-type manner. SFN is a slow-binding inhibitor, following a two-step interaction an complex forms by specific binding of SFN to the active pocket of 3CL^pro, stabilizing the SFN-3CL^pro complex	[27]
49	Myricetin	SARS-CoV-2	Myricetin is an efficient covalent binder of the SARS-CoV-2 3CL^pro	[28]
50	Oridonin	SARS-CoV-2	Oridonin not only effectively inhibited SARS-CoV-2 3CL^pro activity, but also had some inhibitory effects on PL^pro	[29]
51	Prim-O-glucosylcimifugin	SARS-CoV-2	They had strong 3CL^pro inhibitory activities	[30]
52	Rosmarinic acid	SARS-CoV-2
53	Neohesperidin	SARS-CoV-2
54	Osthole	SARS-CoV-2
55	Licoisoflavone A	SARS-CoV-2	Exhibited significant inhibitions against RdRp	[31]
56	Vitisin B	H1N1	Suppresses H1N1 viral replication in MDCK and A549 cells	[33]
57	Quercetin	SARS-CoV-2	Quercetin could be shown to interact with 3CL^pro using biophysical techniques and bind to the active site in molecular simulations	[35, 36]
58	Andrographolide	SARS-CoV-2	Andrographolide was docked successfully in the binding site of SARS-CoV-2 3CL^pro	[37]
59	Chebulagic acid	SARS-CoV-2	By binding to SARS-CoV-2 3CL^pro at a pocket other that substrate binding site, chebulagic acid and punicalagin act as allosteric inhibitors in reversible, noncompetitive manner	[38]
60	Punicalagin	SARS-CoV-2
61	Scutellarein	SARS-CoV-2	Scutellarein was characterized as a potent 3CL^pro inhibitor	[39]
62	4-(2-Hydroxyethyl)phenol	SARS-CoV-2	Inhibit PL^pro by binding at an allosteric S2 site, an interaction and binding region for the Interferon-stimulated gene 15 molecule	[40]
63	4-Hydroxybenzaldehyde	SARS-CoV-2
64	Methyl 3, 4-dihydroxybenzoate	SARS-CoV-2

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Luteolin

SARS-CoV-2

Embrace satisfactory binding to 3CL^pro, and also had good binding to core targets

[13, 14]

β-Sitosterol

SARS-CoV-2

Formononetin

SARS-CoV-2

Anhydroicaritin

SARS-CoV-2

Shinpterocarpin

SARS-CoV-2

Hederagenin

SARS-CoV-2

They had good affinity with the core target 3CL^pro of SARS-CoV-2

[17]

Jaranol

SARS-CoV-2

Linarin

SARS-CoV-2

It had strong binding with 3CL^pro

[20]

DL-Sulforaphane

SARS-CoV-2

[27]

Myricetin

SARS-CoV-2

Myricetin is an efficient covalent binder of the SARS-CoV-2 3CL^pro

[28]

Oridonin

SARS-CoV-2

Oridonin not only effectively inhibited SARS-CoV-2 3CL^pro activity, but also had some inhibitory effects on PL^pro

[29]

Prim-O-glucosylcimifugin

SARS-CoV-2

They had strong 3CL^pro inhibitory activities

[30]

Rosmarinic acid

SARS-CoV-2

Neohesperidin

SARS-CoV-2

Osthole

SARS-CoV-2

Licoisoflavone A

SARS-CoV-2

Exhibited significant inhibitions against RdRp

[31]

Vitisin B

H1N1

Suppresses H1N1 viral replication in MDCK and A549 cells

[33]

Quercetin

SARS-CoV-2

Quercetin could be shown to interact with 3CL^pro using biophysical techniques and bind to the active site in molecular simulations

[35, 36]

Andrographolide

SARS-CoV-2

Andrographolide was docked successfully in the binding site of SARS-CoV-2 3CL^pro

[37]

Chebulagic acid

SARS-CoV-2

By binding to SARS-CoV-2 3CL^pro at a pocket other that substrate binding site, chebulagic acid and punicalagin act as allosteric inhibitors in reversible, noncompetitive manner

[38]

Punicalagin

SARS-CoV-2

Scutellarein

SARS-CoV-2

Scutellarein was characterized as a potent 3CL^pro inhibitor

[39]

4-(2-Hydroxyethyl)phenol

SARS-CoV-2

Inhibit PL^pro by binding at an allosteric S2 site, an interaction and binding region for the Interferon-stimulated gene 15 molecule

[40]

4-Hydroxybenzaldehyde

SARS-CoV-2

Methyl 3, 4-dihydroxybenzoate

SARS-CoV-2

No.	Compound	Antiviral species	Mechanism of action	Ref.
65	Punicalagin	IAV	Punicalgin blocks viral release from the infected cells by inhibiting NA activity	[44]
66	Chebulinic acid	IAV	Exert their inhibitory effect on the NA-mediated viral release	[45]
67	Chebulagic acid	IAV
68	Baicalein	H5N1	Baicalein interfered with the viral NA activity	[46]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Punicalagin

IAV

Punicalgin blocks viral release from the infected cells by inhibiting NA activity

[44]

Chebulinic acid

IAV

Exert their inhibitory effect on the NA-mediated viral release

[45]

Chebulagic acid

IAV

Baicalein

H5N1

Baicalein interfered with the viral NA activity

[46]

No.	Compound	Antiviral species	Mechanism of action	Ref.
69	Epigoitrin	H1N1	Epigoitrin reduced the protein expression of MFN2, which elevated MAVS protein expression and subsequently increased the production of IFN-β and interferon inducible IFITM3	[50]
70	Baicalin	H1N1	Directly induce IFN-γ production in human CD4⁺ and CD8⁺ T cells and NK cells, and activate JAK/STAT-1 signaling pathway	[51]
RSV	The IFN-α and IFN-β in the BALB/c mouse infected by RSV could be evaluated significantly by baicalin	[52]
RSV	The expression of I-IFN in RSV infection rats could be down-regulated by baicalin. The expression of SOCS1/3 might be inhibited by reducing the expression IL-6 and IL-12 by baicalin	[53]
IAV	Baicalin exerts its anti-IVA effect by downregulating miR-146a to subsequently facilitate the type I IFN response	[54]
71	Baicalein	SARS-CoV-2	Baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum	[55]
72	Forsythoside	H1N1	TBK1, IRF3, MAPKp38, and NF-κB p65 in the forsythoside E-treated group were significantly downregulated	[56]
73	Phyllyrin	SARS-CoV-2	Regulation of NF-κB and MAPK signaling pathway and ERK pathways to improve immunity	[17, 57, 58]
74	Cirsimaritin	IAV	Suppress the activation of JNK MAPK and P38 MAPK in vitro, the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-8, and IL-10) and the inflammation-related protein COX-2 were downregulated	[59]
75	Polydatin	SARS-CoV-2	Inhibit macrophage activation in vitro	[60]
76	Isoliquiritin	SARS-CoV-2
77	Ephedrine	SARS-CoV-2
78	Atractylenolide III	SARS-CoV-2
79	Quercetin	RSV	Decreased the levels of TNF-α, IL-6, and IL-1α	[61]
SARS-CoV-2	Quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway	[63]
80	Resveratrol	RSV	Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression	[64]
81	Emodin	SARS-CoV-2	It had good binding ability with the core target of AKT1, IL-6, TP53, JUN, TNF	[65]
82	Lariciresinol-4-O-β-D-glucopyranoside	IAV	Inhibition of NF-κB pathway in influenza A virus-infected alveolar epithelial cells, decrease proinflammatory cytokine expression	[66]
83	Astaxanthin	SARS-CoV-2	Astaxanthin is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α	[67]
84	Watsonianone A	RSV	Watsonianone A inhibited NF-κB activation by suppressing IκBα phosphorylation	[68]
85	Luteolin	H1N1	Reduce the expression levels of the inflammatory cytokines TNF-α, IFN-γ, IL-1 and IL-10, thus reducing the pathological damage	[69]
86	Berbamine	H1N1	Induced activation of the type I interferon pathway	[70]
87	Carotene	SARS-CoV-2	Enter the active pocket of Akt1, prevent lung injury, lung fibrogenesis and virus infection	[71]
88	Kaempferol	SARS-CoV-2
89	Lonicerin	SARS-CoV-2	Inhibition of the arachidonic acid metabolism pathway and preventing the release of inflammatory factors can prevent the cytokine storm	[72]
90	Glycyrrhizic acid	SARS-CoV-2	Heightened release of proinflammatory cytokines IL-1β, IL-6 and IL-8 was attenuated by glycyrrhizin	[73]

No.

Compound

Antiviral species

Compound structure

Mechanism of action

Ref.

Epigoitrin

H1N1

Epigoitrin reduced the protein expression of MFN2, which elevated MAVS protein expression and subsequently increased the production of IFN-β and interferon inducible IFITM3

[50]

Baicalin

H1N1

Directly induce IFN-γ production in human CD4⁺ and CD8⁺ T cells and NK cells, and activate JAK/STAT-1 signaling pathway

[51]

RSV

The IFN-α and IFN-β in the BALB/c mouse infected by RSV could be evaluated significantly by baicalin

[52]

RSV

The expression of I-IFN in RSV infection rats could be down-regulated by baicalin. The expression of SOCS1/3 might be inhibited by reducing the expression IL-6 and IL-12 by baicalin

[53]

IAV

Baicalin exerts its anti-IVA effect by downregulating miR-146a to subsequently facilitate the type I IFN response

[54]

Baicalein

SARS-CoV-2

Baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum

[55]

Forsythoside

H1N1

TBK1, IRF3, MAPKp38, and NF-κB p65 in the forsythoside E-treated group were significantly downregulated

[56]

Phyllyrin

SARS-CoV-2

Regulation of NF-κB and MAPK signaling pathway and ERK pathways to improve immunity

[17, 57, 58]

Cirsimaritin

IAV

[59]

Polydatin

SARS-CoV-2

Inhibit macrophage activation in vitro

[60]

Isoliquiritin

SARS-CoV-2

Ephedrine

SARS-CoV-2

Atractylenolide III

SARS-CoV-2

Quercetin

RSV

Decreased the levels of TNF-α, IL-6, and IL-1α

[61]

SARS-CoV-2

Quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway

[63]

Resveratrol

RSV

Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression

[64]

Emodin

SARS-CoV-2

It had good binding ability with the core target of AKT1, IL-6, TP53, JUN, TNF

[65]

Lariciresinol-4-O-β-D-glucopyranoside

IAV

Inhibition of NF-κB pathway in influenza A virus-infected alveolar epithelial cells, decrease proinflammatory cytokine expression

[66]

Astaxanthin

SARS-CoV-2

Astaxanthin is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α

[67]

Watsonianone A

RSV

Watsonianone A inhibited NF-κB activation by suppressing IκBα phosphorylation

[68]

Luteolin

H1N1

Reduce the expression levels of the inflammatory cytokines TNF-α, IFN-γ, IL-1 and IL-10, thus reducing the pathological damage

[69]

Berbamine

H1N1

Induced activation of the type I interferon pathway

[70]

Carotene

SARS-CoV-2

Enter the active pocket of Akt1, prevent lung injury, lung fibrogenesis and virus infection

[71]

Kaempferol

SARS-CoV-2

Lonicerin

SARS-CoV-2

Inhibition of the arachidonic acid metabolism pathway and preventing the release of inflammatory factors can prevent the cytokine storm

[72]

Glycyrrhizic acid

SARS-CoV-2

Heightened release of proinflammatory cytokines IL-1β, IL-6 and IL-8 was attenuated by glycyrrhizin

[73]