TABLE 3.
Plant derivatives with potential effect on the Spike-RBD/TMPRSS2/ACE2 axis.
| Target | Plant (bioactive phytoconstituent/product) | Study type | Efficacious dose(s) | Biological test | Mechanistic effect | Findings | References | Comment |
|---|---|---|---|---|---|---|---|---|
| Interfere with ACE2 activity | Nicotiana benthamiana domin (recombinant RBD) | In silico and In vitro (vero E6 cells) | NA | Recombinant mAb RBD production in a plant expression system. Neutralization efficiency against positive sera | Binds to ACE2 | Specific binding to the SARS-CoV-2 receptor and its neutralization | Rattanapisit et al. (2020) | Suggested consideration of this plant derived recombinant RBD for the development of vaccines and viral detection/diagnostic reagents |
| Pelargonium graveolens L'Hér. (Citronellol) and Citrus × limon (L.) osbeck (Limonene) a | In vitro (HT-29 cell line) | 50 μg/ml geranium oil and 25 μg/ml lemon oil | Gene expression profile (mRNA and protein) | Downregulates the expression of ACE2 and TMPRSS2 | Significant inhibition of ACE2 and TMPRSS2 in epithelial cells to protect against SARS-CoV-2 invasion | Senthil Kumar et al. (2020) | Citronellol and limonene were the most potent of eight ACE2 inhibitory oil extracts and had dose dependent effects | |
| Momordica dioica roxb. ex willd (catechin, quercetin, hederagenin and oleanolic acid) | In silico and In vitro | NA | Molecular docking and in silico ADME predictions methods | Docking to ACE2 | The constituent bioactive flavonoids (catechin and quercetin) and triterpenoids (hederagenin and oleanolic acid) inhibit ACE2 and DPP4 receptors | Sakshi et al. (2021) | Constituent flavonoids have better affinities than standard remdesivir, favipiravir and hydroxychloroquine | |
| Valeriana jatamansi jones ex roxb. (Hesperidin), Oroxylum indicum (L.) kurz (chrysin), Rheum australe D.Don (emodin) | In silico | NA | Molecular docking and molecular dynamics | Allosterically binds to ACE2 and can also destabilize spike-ACE2 interaction | Ligands (especially hesperidin) triggers conformational changes that causes spike-ACE2 fragment to be unstable | Basu et al. (2020) | Spike inhibitory capacity similar to that of docked chloroquine and hydroxychloroquine | |
| Artemisia absinthium L. (anabsinthin, absinthin, dicaffeoylquinic acids), Syzygium aromaticum (L.) merr. and L.M.Perry (3-0-caffeoylquinic), Phaseolus vulgaris L. (quercetin 3-glucuronide-7-glucoside, quercetin 3-vicianoside, isosakuranetin 7-O-neohesperidoside) and Inula helenium L. (Quercetin-7-O-galactoside, 3,5-dicaffeoylquinic acid, 3,4,5-tricaffeoylquinic acid) | In silico | NA | Molecular modeling/docking and dynamic simulations | High affinity binding to pocket of the active site of ACE2 | Ligands could inhibit viral fusion | Joshi et al. (2020) | Compounds demonstrated good intestinal and brain permeability. Also showed no carcinogenic tendency | |
| Allium sativum L. (diallyl tetrasulfide and trisulfide, 2-propenyl propyl) a | In silico | N/A | Molecular modeling/docking | Binds to ACE2 receptor | Could inhibit viral entry and infectivity | Thuy et al. (2020) | Ligands are the two most potent of seventeen inhibitors of ACE2 gotten from essential oil of plant | |
| Piper sp. (pipercyclobutanamide B, a and nigramide Q) like Piper nigrum L. and Piper retrofractum vahl | In silico | NA | Molecular modeling/docking and dynamic simulations | Docks closely to active site of ACE2 | These dimeric piperamides of essential oil could possibly inhibit ACE2 mediated entry of SARS CoV2 | Gutierrez-Villagomez et al. (2020) | Exhibit potential drug likeness based on ADME. Pipercyclobutanamide B (most potent) docked along duct to ACE2 active site | |
| Ipomoea obscura (L.) ker gawl. (Urso-deoxycholic acid) a | In silico | N/A | Molecular modeling/docking | Bind to ACE2 receptor | Could inhibit viral entry and infectivity | Poochi et al. (2020) | This is the most potent of five possibly bioactive ACE2 inhibitors from ethanolic extract of the plant | |
| Ammoides verticillata (desf.) briq. -From Algeria (isothymol) | In silico | NA | Molecular modeling/docking | Binds to ACE2 receptor | High affinity and can inhibit ACE2 better than captopril and chloroquine drugs | Abdelli et al. (2020) | Suggest oil is one of the richest natural sources of isothymol. Good ADMET | |
| Melaleuca cajuputi maton & sm. ex R. Powell (terpineol, guaiol and linalool) a | In silico | NA | Molecular modeling/docking and dynamic simulations | Latch to the active site of ACE2 | Lots of convergence points and the inhibitory intensity of these compounds on ACE2 could prevent viral invasion | My et al. (2020) | Out of ten inhibitory substances, these three have the most potent effect on ACE2. Guaiol is also present in guaiacum and cypress pine oils | |
| Scutellaria baicalensis georgi (baicalin), Erigeron breviscapus (vaniot) hand-mazz. (Scutellarin), Citrus × aurantium L. and Citrus reticulata blanco (hesperetin), liquorice; Glycyrrhiza uralensis fisch. ex DC. (glycyrrhizin) and soybean; Glycine max (L.) merr. (Nicotianamine) | In silico | NA | Molecular modeling/docking and dynamic simulations | Latch to the active site of ACE2 | Potential to bind ACE2 and hinder viral entry | Chen and Du (2020) | Nicotianamine is “soybean ACE2 inhibitor” (ACE2iSB) | |
| Gancao: Glycyrrhiza spp. and chaihu: Bupleurum spp. (glyasperin F and isorhamnetin) | In silico | NA | Molecular docking | Bind to ACE2 | Latch onto site 1 and site 2 of ACE2 | Ren et al. (2020) | Suggest the ligands, glyasperin F and isorhamnetin, account for strong binding affinity | |
| Interface with the viral spike glycoprotein and its RBD | Liquorice; Glycyrrhiza glabra L. (glycyrrhizic acid) | In silico | NA | Molecular modeling/docking and dynamic simulations | Bind to cavity of prefusion spike glycoprotein | High binding affinity to spike protein may block viral fusion to ACE2 | Sinha et al. (2020a) | High protein-ligand stability. Most potent of six interactive ligands |
| Bupleurum spp., Heteromorpha spp. and Scrophularia scorodonia L. (saikosaponins U and V) a | In silico | NA | Molecular modeling/docking and dynamic simulations | Binds to RBD and cleavage site of the spike glycoprotein | May inhibit viral entry by interfering with virion-receptor binding and protease cleavage | Sinha et al. (2020b) | Out of 23 saikosaponins, had the most potent latching affinity to active site of spike glycoprotein (i.e. RBD) | |
| Indian ginseng: Withania somnifera (L.) dunal (withanoside X and quercetin glucoside) a | In silico | NA | Molecular modeling/docking and dynamic simulations | Binds receptor binding domain of prefusion spike protein from SARS-CoV-2 | Favourable interaction with receptor binding motif (RBM) of RBD to block viral fusion | Chikhale et al. (2020a) | Ligands were potent (out of 17) inhibitors of SARS-CoV-2 spike glycoprotein | |
| Asparagus racemosus willd. (Asparoside D and C) | In silico | NA | Molecular modeling/docking and dynamic simulations | Bind to spike RBD | Good affinity and stable docking of spike RBD | Chikhale et al. (2020b) | Higher binding affinity than remdesivir (standard drug) | |
| Interrupting the spike-rbd/ace2 interaction | Withania somnifera (L.) dunal (withanone) | In silico | NA | Molecular modeling/docking | Interrupts at the junction between ACE2 receptor and viral S-RBD | Decreased binding free energies, destabilized salt bridges, hence blocks and weaken SARS CoV2 entry and infectivity | Balkrishna et al. (2020) | Suggest plant as first choice herb in curbing COVID-19 |
| Diplocyclos palmatus (L.) leaf extract (ripladib) | In silico | NA | Molecular modeling/docking | Interrupts at the RBD of Spike-ACE2 complex | Predicted strong binding at RBD interface to block Spike-ACE2 interactions and viral entry | Alexpandi et al. (2020) | ADMET analysis indicate good pharmacokinetic properties | |
| Citrus spp. (hesperidin) | In silico | NA | Molecular modeling/docking | Binds to both RBD and ACE2 receptor | The flavonoid can possibly interrupt RBD/ACE2 interface to abrogate entry | Utomo et al. (2020) | The peel of Citrus sp. represents the most abundant methoxy flavonoid (hesperidin) store of the plant | |
| Grape skin: Vitis vinifera L. (resveratrol) | In silico | NA | Molecular modeling/docking and dynamic simulations | Bind tightly and interfere with viral S protein/ACE2 receptor complex | Highly stable binding and selectivity to viral protein/ACE2 receptor complex. Disrupts the spike protein | Wahedi et al. (2020) | Most potent of four stilbene-based natural compounds | |
| Interfere with the host membrane protease | Aframomum melegueta K.Schum. (quercetin, apigenin) | In silico and In vitro | 30, 10, 3, 1, 0.3 mg/L. From fruit (with seed) | Docking. In vitro inhibition of recombinant soluble human furin. Immuno-blotting | Disrupts spike glycoprotein/receptor interaction by inhibiting furin cleavage | Metabolites inhibited furin dependent pre-glycoprotein processing by possibly blocking furin recognition site | Omotuyi et al. (2020) | Suggested bioactive influence of flavonoids (like quercetin, apigenin). Good ADMET sores |
| Withania somnifera (L.) dunal (withanone and Withaferine-A) | In silico | NA | Molecular modeling/docking | Binds to TMPRSS2 catalytic site (Wi-N > Wi-A), alters allosteric site and also downregulates TMPRSS2 transcription | Predicted multiple action in blocking SARS CoV2 cell entry and propagation by inhibiting TMPRSS2 | Kumar et al. (2020c) | Possible drug-able agents for prevention and therapeutics |
a
These compounds were found to be the most potent of several others.
Abbreviations: ACE2, Angiotensin converting enzyme two; ADME/T, Absorption, Distribution, Metabolism, Excretion/and Toxicity; DPP4, Dipeptidyl peptidase four; mAb, monoclonal antibody; NA, not available; PK, Pharmacokinetic; S-RBD, Spike glycoprotein receptor binding domain; TMPRSS2, Transmembrane protease serine two; Wi-A, Withaferine-A; Wi-N, Withanone.