Table 1.

Summary of the forty three (43) studies that reported antiviral activity of herbs and natural compounds against the SARS-CoV and other related viruses. Out of the 43 articles, thirty one (31) investigated the mechanisms of action by which the herbs-compounds exerted the antiviral activity, and are marked with a ∗. These molecular mechanisms refer to the action on the coronavirus-host protein pathways (See Fig. 1).

Studies	Tested substances - drugs, medicinal herbs, natural compounds, and synthetic substances	Results - Herbs and natural compounds with antiviral properties
Cinatl et al., 200351	Ribavirin, 6-azauridine, pyrazofurin, mycophenolic acid, and glycyrrhizin were tested for their antiviral properties against CoV isolates (FFM-1 and FF-M2).	Glycyrrhizin or GL (from Glycyrrhiza radix): the most active in inhibiting the replication of SARS-associated virus with few toxic effects. Ribavarin and mycophenolic acid did not affect the replication of the SARS-CoV.
∗Yi et al., 200469	Extracts from 121 Chinese herbs from small molecule libraries that exhibited antiviral activities were screened and tested.	TGG (tetra-O-galloyl-β-D-glucose, from Galla Chinensis) and luteolin avidly binded to SARS-CoV Spike-2 (S2) protein without cytotoxic effects. Quercetin also showed antiviral activity with low cytotoxicity.
Chen et al., 200412	20 commercially antimicrobial agents and the bioactive compounds from “Qing Fei Jie Du Tang” (“Clear the lung and detoxify decoction”) were screened and tested against SARS-CoV isolates: glycyrrhizin (from Glycyrrhiza uralensis), baicalin (from Scutellaria baicalensis), chlorogenic acid (from Flos lonicerae) and artesunate (from Artemisia apiacea). Additional tested drugs: acyclovir, ganciclovir, cidofovir, foscarnet, ribavirin, IFN-α-2a, IFN-α-2b, IFN-β1a, leukocytic IFN-α, amantadine, rimantadine, zidovudine, stavudine, nevirapine, abacavir, ritonavir, and lopinavir.	Glycyrrhizin, baicalin, chlorogenic acid, IFN-β-1a, leukocytic IFN-α, ribavirin, lopinavir, and rimantadine showed antiviral activity. The combination of ribavirin with the IFNs revealed potentially synergistic action against the SARS-CoV. Baicalin instead of glycyrrhizin should be used for prophylaxis or treatment.
Wu et al., 200436	More than 10,000 compounds were screened and tested to identify antiviral agents against the SARS-CoV. The tested substances included approximately 200 FDA-approved drugs, more than 8000 synthetic compounds, around 1000 TCM herbs, and 500 protease inhibitors.	Approximately 50 compounds showed antiviral activity against the SARS-CoV. The most potent compound was Valinomycin. 15 compounds related to Glycyrrhizin and Aescin, and 6 compounds related to Reserpine showed antiviral activity against the SARS-CoV. The extracts of eucalyptus, Lonicera japonica, and ginsenoside-Rb1 showed antiviral activities against the SARS-CoV at a higher concentration (100 μM). The following drugs and compounds did not show antiviral activity against SARS-CoV: AG7088, Pentoxifylline, melatonin, vitamin C, AZT, didanosine, nevirapine, ritonavir, lopinavir, saquinavir, and ribavirin. Ritonavir and Saquinavir did not inhibit SARS-CoV 3CL-PRO.
Hoever et al., 2005111	The anti-SARS-CoV activity of 15 glycyrrhizin derivatives (from Glycyrrhiza radix) was tested.	Seven (7) Glycyrrhizin (GL) derivatives inhibited SARS-CoV replication in-vitro at lower concentrations when compared to GL. Chemical structure modifications to GL caused from a 10-fold to a 70-fold increase in activity against the SARS-CoV.
∗ Lin et al., 200561	Water extract of Isatis indigotica, its 5 major compounds, and 7 phenolic compounds were tested as SARS-CoV 3CLPRO inhibitors (indigo, indirubin, indicant, β-sitosterol, sinigrin, aloe-emodin, hesperidin, quercetin, naringenin, daidzein, emodin, and chrysophanol).	Isatis Indigotica significantly inhibited SARS 3CLPRO. Of the 5 compounds, sinigrin, β-sitosterol, and indigo dose-dependently inhibited 3CLPRO. Sinigrin was more efficient than indigo and β-sitosterol. Aloe-emodin and hesperidin also dose-dependently inhibited the cleavage activity of 3CLPRO. Indigo, sinigrin, and hesperidin showed low cytotoxicity.
∗Chen et al., 2005 (a)37	A library of 720 natural compounds was screened for inhibitory activity against SARS-CoV 3CLPRO. Green, Oolong, Pu’er, and black teas were investigated for the same inhibitory property.	Tannic acid, the polyphenols 3-isotheaflavin-3-gallate, and theaflavin-3,3′-digallate (TF3) found in teas potently inhibited 3CLPRO. The extract from Pu’er and black teas were more potent in inhibiting 3CLPRO than green or oolong teas. Caffeine, theophylline (TP), epigallocatechin gallate (EGCG), epicatechin (EC), catechin (C), epicatechin gallate (ECG), and epigallocatechin (EGC) did not inhibit 3CLPRO at concentrations up to 100 μM.
∗Chen et al., 2005 (b)38	26 Isatin derivative compounds (from Isatis Indigotica) were examined for inhibitory activity against SARS-CoV 3CLPRO.	Some Isatin compounds are potent and selective inhibitors against the SARS-CoV 3CLPRO. Isatin 4o and 4k were especially more potent.
Li et al., 200567	200 Chinese medicinal herbal extracts historically used for the treatment of virus-induced infections were screened for antiviral activities against the SARS-CoV. Interferon-α (IFN-α) was used as a positive control.	Lycoris radiata, Artemisia annua, Pyrrosia lingua, Lindera aggregate, and the compound Lycorine (from L. radiata) showed moderate to potent antiviral activity in a dose-dependent manner. Lycoris radiata was the most potent. Inhibition of the four herbs was stronger than the control IFN-α.
∗Liu & Zhou, 200540	The study screened and tested 8078 compounds from the Marine Natural Products Database (MNPD) and 9127 compounds from the Traditional Chinese Medicine Database (TCMD) to evaluate their molecular docking affinity to the SARS-3CLPRO.	18 compounds, 7 compounds from MNPD and 11 compounds from TCMD showed anti-SARS-CoV 3CLPRO activity (M3927, M4367, M4890, M5410, M5789, M6601, M6602, T1434, T1441, T2826, T2831, T4744, T537, T5656, T6791, T8593, T3091, T5242).
∗Zhou et al., 200641	A series of 23 Isatin derivatives (from Isatis indigotica) were synthesized and tested against the SARS-CoV 3CLPRO.	Isatin compound 5f was the most selective inhibitor against SARS CoV 3CLPRO. It was also a potent inhibitor against HRV-14 3C protease, and it may be used as a broad-spectrum antiviral agent.
∗Chen et al., 200642	8 quercetin-3-β-galatoside derivatives were synthesized and studied for their binding affinity to SARS-CoV 3CLPRO.	Quercetin-3-β-galactoside was identified as a new class of drug and a potent inhibitor of SARS-CoV 3CLPRO.
∗Ho et al., 200772	312 controlled Chinese medicinal herbs were screened for its inhibitory activity against the SARS-CoV Spike (S) protein. Due to a similar chemical structure, emodin was compared to the promazine, an anti-psychotic drug shown to inhibit the replication of SARS-CoV.	Rhei Radix et Rhizoma, Polygoni multiflora radix, and Polygoni multiflora Caulis inhibited the CoV S protein. Also, emodin, an anthraquinone compound derived from Rheum officinalis and Polygonum multiflorum significantly blocked the S protein/ACE-2 interaction in a dose-dependent manner. When compared to emodin, promazine exhibited a higher inhibition, yet differences between them were not significant.
∗Wang et al., 200743	The Traditional Chinese Medicine Database (TCMD) was used to screen more than 10,458 natural molecules. MDL28170 was used as a template as it was shown to inhibit CTSL activity during the entry of the SARS-CoV into the target cell.	MOL 736 (Aurantiamide acetate from Artemisia annua) inhibited the activity of CTSL in the molecular docking analysis. MOL 736 was more “matchable” than MDL28170.
∗Wen et al., 200752	221 phytocompounds were evaluated for activity against the SARS-CoV. Niclosamide and valinomycin were used as controls for their potent anti-SARS-CoV replicative activity.	20 newly identified phytocompounds exhibited significant levels of anti-SARS-CoV activity: 10 diterpenoids, 2 sesquiterpenoids, 2 triterpenoids, 5 lignoids, and curcumin, Betulinic acid and savinin were competitive inhibitors of SARS-CoV 3CLPRO.
∗Lau et al., 200839	The antiviral and immunomodulatory effects of the water extract of Houttuynia cordata were investigated using a murine model.	Houttuynia cordata (HC) exhibited antiviral and immunomodulatory properties that can help prevent the SARS-CoV infection. HC inhibited SARS-CoV 3CLPRO and RdRp, and it was non-toxic after administration to lab animals (16 g/kg).
∗Kim et al., 200893	The effects of 22 medicinal herbal extracts were evaluated for their antiviral activity against CoV (MHV-A59), porcine epidemic diarrhea virus (PDEV), and vesicular stomatitis virus (VSV) in-vitro.	Cimicifuga rhizome, Melia cortex, Coptidis rhizome, Phellodendron cortex, and Sophora subprostrata radix inhibited MHV activity, and reduced viral RNA synthesis, and S and N protein expression. Coptidis rhizome completely abolished MHV production. RNA synthesis was significantly decreased suggesting that the underlying antiviral mechanism might be RdRp inhibition.
Chen et al., 2008112	Formulas-herbs from the TCM classical medical texts Shang Han Lun and Wen Bing Tiao Bian were screened for their possible antiviral activity against the SARS-CoV (strain FFM1) and HCoV 229E. Several other herbs in addition to a popular vegetable Toona sinensis (AKA Cedrela sinensis) were suggested by experienced by TCM doctors for testing.	Only TSL-1, the extract of Toona sinensis Roem was found to have anti-SARS-CoV activity.
Zhuang et al., 200968	The water extract of 7 medicinal herbs was tested for anti-SARS-CoV and anti-ACE-2 properties: Forsythiae fructus, Scutellaria radix, Bupleuri radix, Astragali radix, and Glycyrrhizae radix, and 4 fractionated samples of Cinnamomi cortex (CC) and Caryophylli Flos (CF). The 4 fractions were ethanol (Fr.1), n-butanol (Fr.2), aqueous (Fr.3), and ethylacetate (Fr.4) extractions. Eight (8) compounds isolated from CC were also tested.	Only the extracts of Cinnamomi cortex (CC) and Caryphylli Flos (CF) showed slight to moderate antiviral activity. All CC and CF fractions showed inhibitory activity, but CC/Fr. 2 was the most potent. The CC fractioned compounds procyanidin A2 and procyanidin B1 showed moderate anti-SARS-CoV activity. The compounds did not affect ACE-2.
∗Ryu et al., 2010 (a)44	12 phytochemicals (8 diterpenoids and 4 biflavonoids) were isolated from Torreya nucifera and examined for their anti-3CLPRO activity. Abietic acid, apigenin, luteolin, and quercetin were also evaluated.	The ethanol extract of Torreya nucifera exhibited inhibitory activity against 3CLPRO. From the diterpenoids, ferruginol (3) was the strongest anti-SARS-CoV 3CLPRO. Among the isolated bioflavonoids, amentoflavone (9) was the most potent inhibitor of SARS-CoV 3CLPRO. Apigenin, luteolin, and quercetin were also strong inhibitors.
∗Ryu et al., 2010 (b)45	Isolated quinone-methide triterpenes (celastrol, pristimerin, tingenone, iguesterin) from Tripterygium regelii, and the semi-synthetic dihydrocelastrol were evaluated for anti-SARS-3CLPRO activity. Curcumin was used as a positive control which is known to inhibit 3CLPRO.	Tripterygium regelli remarkably inhibited SARS-CoV 3CLPRO activity (>70% inhibition at 30 μg/ml). Celastrol, pristimerin, tingenone, and iguesterin showed potent anti-SARS-3CLPRO activity, and dihydrocelastrol also showed SARS-3CLPRO inhibitory activity, although less.
∗Kim et al., 201059	19 TCM herbal extracts were evaluated for antiviral activity against MHV-A59. The extracts were also tested against the John Howard Mueller strain of MHV (MHV-JHM), porcine diarrhea virus (PEDV), and vesicular stomatitis virus (VSV). Ribavirin was used as a control.	Sophorae radix, Acanthopanacis cortex, Sanguinobae radix, and Torilis fructus showed in-vitro antiviral activity reducing or completely inhibiting MHV-A59. All 4 herbs were stronger CoV inhibitors than ribavirin. Sophorae radix had the highest selectivity index. Sophorae radix, Acanthopanacis cortex, and Torilis fructus reduced mRNA7 and N protein synthesis, while Sanguinobae radix only decreased N protein synthesis without significant reduction in intracellular RNA levels.
∗Schwarz et al., 201135	Emodin was investigated for anti-SARS-CoV 3a protein in-vivo and in-vitro.	Emodin is a potent inhibitor of 3a ion channel of SARS-CoV and HCoV-OC43. In the plaque reduction assay emodin showed antiviral property in a dose-dependent manner. Emodin at 100 μM inhibited viral release by 20% and with 100 μM it completely inhibited viral release.
∗Wen et al., 201164	More than 200 extracts from Chinese medicinal herbs were evaluated for anti-SARS-CoV activity. Valinomycin was used as reference control with high inhibition. For the SARS-CoV 3CL inhibition assay, niclosamide was used as a reference control.	The herbal extracts of Gentiana radix (GSH), Dioscorea rhizome (DBM), Cassiae semen (CTH), Loranthi ramus (TCH), and CBE and CBM (extracts from Rhizoma cibotii, the root of Cibotium barometz) were potent inhibitors of SARS-CoV with little or no cytotoxicity. Although the valinomycin was more potent, these 6 herbs significantly inhibited SARS-CoV. CBM and DBM showed significant inhibition of SARS-CoV 3CLPRO activity.
Yin et al., 2011113	Houttuynia cordata (HC) was investigated in-vitro, in-vivo and in-ovo for antiviral properties against the avian infectious bronchitis virus (IBV). Also, the effect of HC on cell apoptosis induced by IBV was investigated.	Houttuynia cordata had more than 90% inhibition rate against the IBV infection, and decreased more than 90% apoptotic cells caused by the virus. The inhibitory effects of HC on IBV infection in-ovo protected the SPF embryos from death with no adverse effects. However, the treatment of chickens with HC did not fully protect against IBV.
∗Yu et al., 201265	The researchers examined 64 purified natural compounds against the SARS-CoV helicase (nsP13) protein and the HCV helicase.	Myrecetin and Scutellarin (from Scutellaria Baicalensis) potently inhibited the SARS-CoV helicase protein in-vitro by affecting ATPase activity by more than 90% at a concentration of 10 μM, but with no unwinding activity or cytotoxicity. Other compounds such as myricitrin, amentoflavone, diosmetin-7-O-Glc-Xyl, and taraxerol also inhibited nsP13.
Chang et al., 201253	23 compounds were isolated from Euphorbia neriifolia L., including 22 triterpenoids and 1 flavonoid glycoside, and tested for their antiviral activity against the human coronavirus (HCoV-229E). Actinomycin D was used as a positive control.	13 new compounds were isolated from Euphorbia neriifolia L. for the first time. 3β-Friedelanol exhibited more potent anti-viral activity (132.4%) than the positive control, Actinomycin D (69.5%).
∗Park et al., 201263	Seven tanshinone isolates from Salvia miltiorrhiza were investigated for SARS-CoV 3CLPRO and PLPRO inhibition, and deubiquitinating (DUB) enzyme activities. Tanshinones: tanshinone IIA (1), tanshinone IIB (2), methyl tanshinonate (3), cryptotanshinone (4), tanshinone I (5), dihydrotanshinone I (6), and rosmariquinone (7).	The ethanol extract from Salvia Miltiorrhiza inhibited both proteases SARS-3CLPRO (60%) and PLPRO (80%) at 30 μg/ml. The tanshinone compounds (1-7) showed marked inhibitory activity against the SARS-CoV 3CLPRO and PLPRO. The isolate tanshinone I (5) exhibited the most potent inhibitory activity toward deubiquitinating.
∗Park et al., 201346	The study investigated 9 phlorotannins (1-9) isolated from the edible algae Ecklonia cava for their anti-SARS-3CLPRO inhibitory activity. Isolated compounds: 1. Phloroglucinol, 2. Triphloretol, 3. Eckol, 4. Dioxinodehydroeckol, 5.2-phloroeckol, 6.7-phloroeckol, 7. Fucodiphloroethol, 8. Diecklo, 9. Phlorofucofuroeckol.	Isolates 2-9 of Ecklonia cava showed SARS-CoV 3CLPRO inhibitory activity in a dose-dependent and competitive manner with no toxicity. Dieckol (8) showed the most potent anti-SARS-CoV 3CLPRO activity.
∗Cho et al., 201395	The study investigated the SARS-CoV PLPRO inhibitory activities of the methanol extract of Paulownia tomentosa fruits and its 12 flavonoid (1-12) isolates.	Most compounds (1-12) from P. tomentosa inhibited SARS-PLPRO in a dose-dependent manner in-vitro. All the newly discovered geranylated flavonoid compounds (1-5) (tomentin A, tomentin B, tomentin C, tomentin D, tomentin E) showed better inhibition than their parent compounds.
∗Schwarz et al., 201466	The researchers tested the inhibitory activity of the flavonols kaempferol, kaempferol glycosides, and acylated kaempferol glucoside derivatives against the SARS-CoV 3a protein in-ovo. Other flavonoids such as quercetin, naringenin, and genistein were also tested.	Five (5) kaempferol glycosides (kaempferol, juglanin, tiliroside, afzelin, and Kaempferol-3-O-α-rhamnopyranosyl(1 → 2) [α rhamnopyranosyl(1 → 6)]-β-glucopyranoside) inhibited 3a protein. Juglanin was a potent 3a protein inhibitor and produced nearly complete inhibition (10 μM) or complete inhibition (20 μM). The kaempferol glycosides tiliroside and afzelin, although less potent than juglanin, also inhibited 3a protein. Quercetin, naringenin, and genistein did not affect 3a protein.
∗Liu et al., 201447	A series of 5-sulfonyl isatin derivatives (from Isatis indigotica) were designed, synthesized and evaluated for anti-SARS-CoV 3CLPRO activity.	A series of compounds showed inhibitory activity against SARS-3CLPRO. Compounds 7a-m, 7i and 7 k showed the highest inhibition. Among the compounds 8, 8k1 and 8k2 were the most potent. Compounds 3f and 3h showed high inhibitory activities (95.32% and 95.37%).
∗Song et al., 201496	The methanol extract of Tribulus terrestris fruits and the fractioned 6 cinnamic amides (1-6) and ferulic acid (7) were investigated for anti-SARS-CoV PLPRO activity. Compounds: 1. N-trans-caffeoyltyramine, 2. N-trans-coumaroyltyramine, 3. N-trans-feruloyltyramine, 4. terrestriamide, 5. N-trans-feruloyloctopamine, 6. terrestrimine, and 7. ferulic Acid.	T. terrestris showed potent activity against SARS-CoV PLPRO. Compounds 1-6 displayed significant PLPRO inhibitory activity. Terrestrimine (6) was the most potent, and ferulic acid was inactive against PLPRO up to 200 μM.
Chiow et al., 201662	The study evaluated the activities of ethyl acetate (EA) fraction of Houttuynia cordata and three of its flavonoids, quercetin, quercitrin, and rutin against the SARS-CoV and Dengue using the MHV and DEN-2 virus models. The compounds were compared with Cinanserin hydrochloride which was proven to neutralize SARS-CoV in-vitro.	The EA fraction of Houttuynia cordata inhibited both MHV and DEN-2 in-vitro. HC exerted antiviral activity with no cytotoxicity in-vitro and in-vivo. Quercetin also inhibited both MHV and DEN-2. Quercetrin inhibited DENV-2, but not MHV. Rutin did not show an inhibitory effect on both viruses.
∗Park et al., 201648	The isolates of Angelica keiskei, 9 ankylated chalcones (1-9) and 4 coumarins (10-13) were examined for their anti-SARS-CoV 3CLPRO and PLPRO activity. Compounds: isobavachalcone (1), 4-hydroxyderricin (2), xanthoangelol (3), xanthoagenol F (4), xanthoangelol D (5), xanthoangelol E (6), xanthoangelol B (7), xanthoangelol G (8), xanthokeistal (9), psoralen (10), bergapten (11), xanthotoxin (12), isopimpinellin (13).	The ethanol extract of Angelica keiskei significantly inhibited 3CLPRO (75% inhibition at 30 μg/ml) and PLPRO (88% at 30 μg/ml). All of the isolated compounds (1-13) except the coumarin derivatives (10-13) showed a dose-dependent inhibitory activity against the SARS-CoV 3CLPRO. Chalcone 6 (xanthoangelol E) exhibited the most potent anti-SARS 3CLPRO and PLPRO inhibitory activity. All 13 isolates also showed potent activity against ubiquitin and ubiquitin-like proteins.
∗Park et al., 201790	The study investigated the inhibitory activity of Broussonetia papyrifera-derived polyphenols against SARS-3CLPRO and PLPRO in-vitro. Isolated compounds: broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 30-(3-methylbut-2-enyl)-30,4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), kazinol J (10). Additionally, isoliquiritigenin, kaempferol, quercetin and quercetin-β-galactoside were also tested.	All polyphenols (1-10) were potent inhibitors of SARS-PLPRO, more than against 3CLPRO. Compound 4 (papyriflavonol A) was the most potent against SARS-CoV PLPRO and presented the highest deubiquitination and deISGylation inhibitory activity.
∗Kim et al., 2019108	The study evaluated the antiviral properties against the compounds isolated from Stephania tetrandra and other related species of Menispermaceae against the HCoV-OC43. Compounds: bis-benzylisoquinoline alkaloids-tetrandine (TET), fangchinoline (FAN), and cepharanthine (LEP).	Stephania tetandra, TET, FAN, and LEP significantly inhibited HCoV-O43 replication in a time- and dose-dependent manner with no cytotoxicity even with high concentrations. The three compounds inhibited S and N protein expression, and experiments indicated that they can be applied for the prevention and treatment of HCoV infection. Compounds also reduced the expression of the cytokines IL-1β, IL-6 and IL-8.
Weng et al, 2019109	The study investigated the antiviral activity of ethanol extract of Sambucus FormosanaNakai stem and some phenolic constituents against the HCoV-NL63 in-vitro. Phenolic acid constituents: caffeic acid, chlorogenic acid, coumaric acid, ferulic acid, and gallic acid.	S. FormosanaNakai inhibited HCoV-NL63 virus yield, plaque formation, and viral attachment with low toxicity in a concentration-dependent manner. The in-vitro antiviral activity was ranked according to virus yield reduction: caffeic acid > chlorogenic acid > coumaric acid. Caffeic acid was the strongest inhibitor of HCoV-NL63 and powerfully reduced the viral attachment to the cell surface and plaque formation.
Shen et al., 201960	A 2000-compound library of FDA-approved drugs and pharmacologically active compounds were screened for an in-vivo and in-vitro study to assess the broad-spectrum antiviral properties against the HCoV-OC43, HCoV-NL63, MERS-CoV, and MHV-A59. Control: dimethyl sulfoxide (DMSO)	The in-vitro antiviral activity of 36 compounds against wild-type HVoV-OC43 was confirmed. 17 compounds inhibited HCoV-NL63, 13 compounds inhibited MERS-CoV, and 12 compounds inhibited MHV-A59. 7 compounds were identified as broad-spectrum inhibitors of the 4 CoVs in-vitro in a dose-dependent manner (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate). All 7 compounds significantly inhibited HCoV-OC43 (90% inhibitory effect). Lycorine (from Lycoris radiata) was the most potent antiviral compound against all 4 viruses.
∗Tsai et al., 2020114	This study investigated the antiviral activity of the methanol extract of Strobilanthes cusia leaf and its chemical components against the anti-HCoV-NL63. The researchers also investigated the anti-RdRp and anti-PLPRO activity of the compounds. S. cusia components: β-sitosterol, indirubin, tryptanthrin, betulin, indigodole A, and indigodole B.	S. cusia potently inhibited virus yield and viral infectivity of HCoV-NL63-infected cells in a concentration-dependent manner. Tryptanthrin showed the strongest antiviral activity. It prevented the early and late stages of viral replication and significantly inhibited RdRp and PLPRO 2 activity. Indigodole B was the second-highest to reduce HCoV-NL63. Both tryptanthrin and indigole B showed low cytotoxicity.
∗Zhang et al, 202050	A literature search for natural compounds with confirmed anti-SARS-CoV or MERS-CoV activity was conducted. The resulting compounds were cross-checked with the TCM Systems Pharmacology Database. The study aimed to identify compounds that would be potentially protective against the SARS-CoV-2 (2019).	The antiviral activity of 115 natural compounds was confirmed. After Absorption, Distribution, Metabolism, and Excretion (ADME) evaluation, thirteen (13) compounds were found to have anti-SARS-CoV-2 (2019) activity. 125 herbs contained one or more of these 13 compounds. Of these 125 herbs, 26 are classically cataloged to treat viral respiratory infections. For all plants analyzed, nearly half of the top 30 pathways are related to antiviral, immune, inflammatory and hypoxia responses indicating that these herbs are suitable for antiviral use. Molecular docking identified a series of compounds that inhibited 3CLPRO, PLPRO and S protein (see Fig. 1). TCM classical treatments used for viral respiratory infections might contain direct anti-2019-nCoV compounds.
∗Khan et al., 202049	Database of natural and synthetic molecules and 16 FDA-approved drugs were screened and tested for their inhibitory activity against SARS-CoV-2 3CLPRO.	Remdesivir, Saquinavir, Darunavir, and the natural compounds flavone and coumarin derivatives exhibited inhibitory activity against SARS-CoV 3CLPRO. Saquinavir showed the highest binding affinity.
∗Wu et al., 20202	Molecular docking simulations were performed to identify the drugs, herbs, natural compounds, and synthetics that would inhibit/block 3CLPRO, PLPRO, RdRp, helicase, Spike protein, ACE-2, and other protein pathways of the SARS-CoV-2. Several databases were screened such as the FDA approved drug database (ZINC drug database) containing 2924 compounds, TCM herbs and natural products database including reported common antiviral components with 1066 substances, and database of commonly used antiviral drugs containing 78 antiviral compounds. The complete genome of the Wuhan-Hu-1 SARS-CoV was downloaded from the NCBI nucleotide database and used for this study. Studies on the homology encoded proteins of the SARS-CoV-2 in comparison with the SARS-CoV-1 were performed.	For the mechanisms of action of the herbs and natural compounds onSARS-CoV-2, seeFig. 1. Drugs that may inhibit SARS-CoV-2 PLPRO: ribavirin, valganciclovir, β-thymidine (antiviral); doxycycline, chloramphenicol, cefamandole, tigecycline (antibacterial); chlorphenesin carbamate (muscle relaxant); and levodropropizine (anti-tussive), and others. Also, l(+)-Ascorbic acid, glutathione, hesperidin and sildenafil (for erectile dysfunction) showed potential as PLPRO inhibitors. Drugs that may inhibit 3CLPRO:lymecycline, chlorhexidine, demeclocycline, doxycycline, tigecycline, oxytetracycline (anti-bacterial); alfuzosin, nicardipine, telmisartan (anti-hypertensive); and conivaptan (used for hyponatremia), and others. Montelukast (asthma medication) and lutein also showed potential as 3CLPRO inhibitor. Potential drugs inhibitors of SARS-CoV-2 RdRp: valganciclovir (antivirus), itraconazole (anti-fungal); chlorhexidine, ceftibuten, cefuroxime, novobiocin (antibacterial); atovaquone (antimalarial), chenodeoxycholic acid (gall-dissolving drug); cortisone (anti-allergic); fludarabine, idarubicin (anti-tumor); silybin (hepatoprotective); pancuronium bromide (muscle relaxant); dabigatran etexilate (anti-coagulant), and others. Drugs that would inhibit SARS-CoV-2 helicase protein: lymecycline, cefsulodine, rolitetracycline (antibacterial); itraconazole (anti-fungal); saquinavir (anti-HIV-1); dabigatran (anti-coagulant); and canrenoic acid (diuretic). Possible SARS-CoV-2 anti-Spike protein drug inhibitors: rescinnamine, iloprost, prazosin (anti-hypertensive); poconazole, itraconazole (anti-fungal); sulfasalazine, azlocillin, penicillin, cefsulodin (antibacterial); and dabigatran etexilate (anti-coagulant). Drugs that may inhibit Nsp1, Nsp3c, and ORF7a: piperacillin, cefpiramide, streptomycin, lymecycline, and tetracycline. Potential host ACE-2 inhibitors: troglitazone (anti-diabetes), losartan (anti-hypertensive), ergotamine (analgesic), cefmenoxime (anti-bacterial), and silybin (hepatoprotective). Potential TMPRSS2 inhibitors: pivampicillin, hetacillin, cefoperazone, and clindamycin (antibacterial).