Abstract
Natural Product Communications Special Collection “Phytochemicals against SARS-COV-2 Infection” accepted 13 manuscripts, represented by 2 reviews, 9 original articles, and 1 letter to the editor. These deal with the use of traditional medicines, the use of network pharmacology, and docking studies to identify active compounds with prominent binding to various receptors responsible for internalization and replication, such as ACE2, S-protein, Mpro, PLpro, RdRp, and NSP15 endoribonuclease, as well as the possible use of phytochemicals against virus-associated inflammation.
Keywords
Infectious coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the largest challenges in medicine and public health due to its management being hampered by the lack of antivirals capable of reducing virus replication without side effects. Drug repurposing of available and well-tolerated drugs that actively impair virus replication at the early stages of infection represents a promising option. Several studies that have been conducted on the antiviral and anti-inflammatory effects of natural products and herbal medicines have shed some light on their mechanism of action and possible targets, like viral entry, replication, assembly, release, and virus–host specific interactions. Treatments with natural products do not replace vaccines and other non-pharmaceutical measures, but they are practical, empirical, and effective measures that can slow down viral replication, reducing mortality, morbidity, and collateral damage from COVID-19 infection. Supplementation with phytochemicals should be considered in prophylaxis and as a means to alleviate side effects of COVID-19 vaccines. With all of these points in mind, we invited the scientific community to contribute original research articles, as well as comprehensive review articles, on the utilization of natural products as possible antivirals and their potential as anticoronaviral agents.
Traditional medicines have been widely employed for the treatment of viral infection. In this relation the mechanism for Qing-Fei-Pai-Du Decoction has been studied via network pharmacology and molecular docking. The flavonoids quercetin, kaempferol, and wogonin were identified as main active components, through their actions on multiple biological pathways. 1
The active components of Shiwei Qingwen decoction (SWQWD) and its potential targets for preventing COVID-19 were studied by network pharmacology and molecular docking. These studies suggest quercetin, kaempferol, and luteolin as the most potent compounds which may enhance immunity by regulating multiple TNF signal pathways. After administering SWQWD, the content of tumor necrosis factor-α was significantly reduced in the bronchoalveolar lavage fluid of ALI rats in comparison to the model group, and thus SWQWD may be effective in preventing COVID-19. 2
Based on bioinformatics and computational chemistry methods, Jiedu Huoxue Decoction (JHD), a Chinese traditional prescription for patients with severe COVID-19, quercetin, luteolin, β-sitosterol, puerarin, stigmasterol, kaempferol, and wogonin were identified as the key phytochemicals. The hub genes included IL6, IL10, VEGFA, IL1B, CCL2, HMOX1, DPP4, and ACE2. ACE2 and DPP4 were related to SARS-CoV-2 entering cells. The molecular docking studies confirmed that the conformations of the puerarin-ACE2, quercetin-EGFR, luteolin-EGFR, and quercetin-IL1B complexes were stable, and thus JHD could treat COVID-19 by intervening in cytokine storm, thrombosis, and the entry of SARS-CoV-2, while regulating the immune system. 3
The rich diversity of African medicinal plants and their chemical compounds with antiviral, anti-inflammatory, and immunomodulatory activities, and COVID-19 symptom relieving effects has been reviewed by Akindele et al. The review provides baseline information on the pharmacological activities, toxicity, and chemical components of 9 plants (Bryophyllum pinnatum, Aframomum melegueta, Garcinia kola, Sphenocentrum jollyanum, Adansonia digitata, Sutherlandia frutescens, Hibiscus sabdariffa, Moringa oleifera, and Nigella sativa), making them potential candidates for further investigation for effectiveness against COVID-19. 4
In another review by Sharma et al, the authors have reviewed herbal drugs and their constituents exhibiting antiviral properties. They recommended clinical studies to be performed using phytoconstituents, such as hesperidin, emodin, artemisinin, lycorine, and lianhuaqingwen, as these have shown exciting anti-SARS-CoV efficacy. However, still more phytoconstituents should be studied through proper clinical trials to find more effective anti-SARS-CoV treatments. 5
Angiotensin-converting enzyme 2 (ACE2), an entry receptor of the SARS-CoV-2 virus, is also responsible for various neurological dysfunctions that are associated with COVID-19 in patients. To treat the neurological manifestations associated with the ACE2 receptor, Hou et al discerned that andrographolide and 14-deoxy-11,12-didehydroandrographolide, constituents of Andrographis paniculata, bind effectively with the ACE2 receptor and must be further clinically validated for treating neurological manifestations associated with the ACE2 receptor in COVID-19. 6
In another study, the inhibitory potential of ginsenosides was investigated against the 6 vital SAR-CoV-2 host entry-related proteins ACE2, Spike RBD, ACE2 and Spike RBD complex, Spike (pre-fused), Spike (post-fused), and HR domain. Almost all the ginsenosides showed low binding energies and were found to be favorable for efficient docking and resultant inhibition of the viral proteins. The top 5 ginsenosides: floral ginsenoside P, ginsenoside Rh1(S), ginsenoside Ra1, ginsenoside Rg7(R), and ginsenoside Rg3(R), with high binding energy with ACE2, interacted with several hotspot residues of ACE2 through hydrophobic and hydrophilic bonding. In conclusion, ginsenosides were suggested to be potential natural inhibitors of SARS-CoV-2 related proteins. 7
Wang et al explored the potential mechanisms and efficacy of polydatin against COVID-19 by the combined application of network pharmacology, molecular docking, and an experimental verification approach. They suggested that polydatin may alter the immune, cytokines, and inflammatory responses, as well as SARS-CoV-2 innate immunity evasion and cell-specific immune response. Furthermore, polydatin can potentially bind to SARS-CoV-2 Mpro, RdRp, and ACE2. The experimental results showed that polydatin decreased the infectivity of the SARS-CoV-2 spike pseudovirus in HEK293T-ACE2 cells, thus retarding the entry of SARS-CoV-2 into the cells. 8
In a pharmacophore-based virtual screening study, pharmacophore models for SARS-CoV-2 Mpro inhibitors were constructed based on 24 diverse compounds with varying levels of activity. The best pharmacophore (Hypo1) was then employed as a query for virtual screening of molecules from an in-house natural product database and 1502 hits were identified which were further analyzed using drug-like filters and SARS-CoV-2 Mpro-inhibitory activity analysis. Finally, one hit (W-7) showed effective biological activity, with an IC50 value of 75 μM. Molecular docking was performed to understand the interaction between this hit compound and SARS-CoV-2 Mpro, and results show that the hit W-7 may act as a good lead against SARS-CoV-2 Mpro. 9
Evodiamine (Evodia constituent) and its derivatives were investigated via virtual screening and molecular dynamics for identifying potential inhibitors of the SARS-CoV-2 main protease and the promising hits were docked into the binding site of the enzyme. 13-(4-Chlorobenzoyl)-10-hydroxy-14-methyl-8,13,13b,14-tetrahydroindolo[2′,3′ :3,4] pyrido[2,1-b]-quinazolin-5(7H)-one interacted favorably with the enzyme; it showed the highest binding ability and its structure occupied most of the binding pocket as for the co-crystallized inhibitor MPI5 with the main protease. 10
Lu et al investigated 1025 compounds, and of these 181 were selected for molecular docking analysis. Four phytochemicals: licorice glycoside E, diisooctyl phthalate, (-)-medicocarpin, and glycyroside, exhibiting good binding affinity with RdRp, and of these licorice glycoside E was identified as best due to 3 hydrogen bonds, 4 hydrophobic interactions, 1 pair of pi-cation/stacking, and 4 salt bridges. 11 In silico study has shown a good performance of the N-{2-[(2S)-2-amino-3-methylbutoxy]-6-propylbenzoyl}-L-phenylalanyl-L-serine (Butoxypheser), which acts against multiple target proteins: main protease, spike protein, NSP15 endoribonuclease, RNA-dependent RNA polymerase, and papain-like protease, which suggests that it can be used effectively against SARS-CoV-2 infection. 12
SARS-CoV-2 spike protein-induced heart inflammation may originate from either COVID-19 infection or the administration of COVID-19 mRNA vaccines. It has been suggested that supplementation with pyrroloquinoline quinone (PQQ), a scavenger of free radicals, redox cofactor, and antioxidant, which supports cognitive and mitochondrial functions, could have a positive effect to reduce heart inflammation after COVID-19 mRNA vaccines. 13 However, further studies are needed with appropriate clinical trials.
Computational studies targeting the identification of key chemical signatures involved in the antiviral properties and/or identified in traditional systems have shed light on possible mechanisms and bindings with various protein targets.
In summary, we are confident that the members of community of natural product researchers will find this Special collection exciting for their own research in the near future and would like to thank all of the authors who have contributed interesting and important articles to this collection and reviewers for their invaluable comments to the authors.
