key: cord-0700209-lkpojgvm
authors: Merarchi, Myriam; Dudha, Namrata; Das, Bhudev C; Garg, Manoj
title: Natural products and phytochemicals as potential anti‐SARS‐CoV‐2 drugs
date: 2021-06-16
journal: Phytother Res
DOI: 10.1002/ptr.7151
sha: 72c759031f291465ca004b33aa6a3787ba3480c1
doc_id: 700209
cord_uid: lkpojgvm

The current pandemic responsible for the crippling of the health care system is caused by the novel SARS‐CoV‐2 in 2019 and leading to coronavirus disease 2019 (COVID‐19). The virus enters into humans by attachment of its Spike protein (S) to the ACE receptor present on the lung epithelial cell surface followed by cleavage of S protein by the cellular transmembrane serine protease (TMPRSS2). After entry, the SARS‐CoV‐2 RNA genome is released into the cytosol, where it highjacks host replication machinery for viral replication, assemblage, as well as the release of new viral particles. The major drug targets that have been identified for SARS‐CoV‐2 through host‐virus interaction studies include 3CLpro, PLpro, RNA‐dependent RNA polymerase, and S proteins. Several reports of natural compounds along with synthetic products have displayed promising results and some of them are Tripterygium wilfordii, Pudilan Xiaoyan Oral Liquid, Saponin derivates, Artemisia annua, Glycyrrhiza glabra L., Jinhua Qinggan granules, Xuebijing, and Propolis. This review attempts to disclose the natural products identified as anti‐SARS‐CoV‐2 based on in silico prediction and the effect of a variety of phytochemicals either alone and/or in combination with conventional treatments along with their possible molecular mechanisms involved for both prevention and treatment of the SARS‐CoV‐2 disease.

cases of SARS-CoV-2 with 1.9 million deaths worldwide have been confirmed by World Health Organization (WHO) official statistics (Bai et al., 2021) . Although it comes from the same lineage, which has been responsible for SARS, however, this virus shows only 79% similarity with SARS-CoV and 50% with MERS-CoV (Lu et al., 2020; Rabaan et al., 2020) . SARS-CoV-2 is believed to be transmitted to humans by zoonotic transfer, from insectivorous bats (Rhinolophus affinis) or pangolins (Manis javanica), and interestingly, more than 96% of the genome sequencing of SARS-CoV-2 was identical to the one of the bat CoV RaTG13 (Pagano, 2021; Shereen, Khan, Kazmi, Bashir, & Siddique, 2020; Zhou et al., 2020) . SARS-CoV-2 is an enveloped, non-segmented, single strands positive-sense RNA virus with crown-like spikes on the viral outer membrane (Watanabe, Allen, Wrapp, McLellan, & Crispin, 2020) . It has a diameter of 65 to 125 nm with a length of 29.9 kb (Shereen et al., 2020) . The viral genome is transcribed into 16 non-structural proteins (nsPs) and four main structural proteins (sPs). The structural proteins have been identified as spike glycoprotein (S), small envelope glycoprotein(E), membrane glycoprotein(M), and nucleocapsid protein (N) (Y. Chen, Liu, & Guo, 2020; Shereen et al., 2020; Walls et al., 2020) that is transcribed by the sub-genomic RNA of the virus. The S glycoprotein is a transmembrane protein with a molecular weight of about 150 kDa localized in the virus outlying membrane. S protein constitutes a homo-trimers in the viral surface and allows the binding of the SARS-CoV-2 envelope to the host cells by attaching with angiotensinconverting enzyme 2 (ACE2) that is expressed in various cells types, including respiratory cells, myocardial cells, and kidney cells (Lan et al., 2020; Watanabe et al., 2020) . Hence, patients who are infected with SARS-CoV-2 might develop respiratory syndromes such as pneumonia (Gibson, Qin, & Puah, 2020) , which may lead to Acute Respiratory Distress Syndrome (ARDS). Apart from that, patients might also develop cardiac, hepatic, and digestive disorders. S protein is fragmented by the virus-host cell furin-like protease into two subunits known as S1 and S2. S1 would determine the host-virus range and cellular tropism with the receptor-binding domain make-up while S2 is the fusion intermediate with the host cells (Rabaan et al., 2020; Walls et al., 2020) . The N protein constitutes the nucleocapsid of the virus and is capable of binding to the viral RNA through its C-terminal as well as N-terminal domains. Due to the binding of the protein with the viral RNA, it is implicated in processes related to the viral genome, that is, the viral replication cycle, and the cellular response of host cells to viral infections (Schoeman & Fielding, 2019) . Furthermore, N protein is highly phosphorylated and it has been proposed that phosphorylation triggers a structural change in the protein, which increases its affinity for the viral RNA (Chen, Liu, & Guo, 2020) . In addition, it has been shown to interact with nsP3 and M protein suggesting its role in viral replication as well as packaging. M protein of the coronaviruses is the key structural protein of the viral envelope. Its interaction with nucleocapsid is crucial for the coronavirus assembly (Neuman et al., 2011; Sturman, Holmes, & Behnke, 1980) . The selfinteraction of M proteins helps in the maintenance of the viral scaffold. Lastly, the E protein, which is the smallest protein in the SARS-CoV-2 structure has a central function in viral morphogenesis and assembly (Bianchi et al., 2020) . Viroporins affects the viral entry into the host cell besides its production and maturation (Bianchi et al., 2020) . SARS-CoV-2 infection is triggered by the recognition and binding of the virus particle to the human ACE2 after which fusion of the virus and its host cellular membrane occurs (Chakraborty & Bhattacharjya, 2020; Wu et al., 2020) . ACE 2 is a type 1 membrane protein localized in the lung, kidney, intestine, and heart. This protein is crucial for the maturation of angiotensin (a hormone that regulates vasoconstriction and blood pressure). The fusion between the viral envelope and host cell surface is mediated by the viral transmembrane fusion protein.

Depending on the availability of proteases, coronavirus has two routes for entry and membrane fusion. First is the early pathway, which is adopted by the virus if the plasma protease like TMPRSS2 is available, and the virus fuses with the host membrane releasing the virus in the cytoplasm (Hoffmann et al., 2020; Simmons, Zmora, Gierer, Heurich, & Pohlmann, 2013) . Further, Spike protein S also undergoes a conformational change and is primed by TMPRSS2 for membrane fusion (Figure 1 ) (Hoffmann et al., 2020; Simmons et al., 2013) . If the membrane proteases are absent, then the coronavirus will be embodied by clathrin or non-clathrin mediated endocytosis and this is referred to as the late pathway. In the latter pathway, activation of cathepsin L influences the viral-host membrane fusion at the endosomal membrane. It has been demonstrated that protease availability and cell type govern the virus entry not only in SARS-CoV-2 but also in SARS-CoV and MERS-CoV. Once in the host cell, SARS-CoV2 releases mRNA and takes over the host replication machinery to facilitate viral replication. SARS-CoV2 genome, like other coronaviruses, is approximately 30 kb long positive single-stranded, non-segmented RNA molecule with 5 0 cap and 3 0 poly-A tails. The viral genome during translation undergoes À1 ribosomal frameshift creating ORF1a and ORF1b. These two ORFs are translated into two polypeptides namely pp1a and pp1b. These two polypeptides are further processed by viral proteases to form 16 nonstructural proteins (nsPs) of which the first 11 nsPs are coded by ORF1a while ORF1b encodes nsP12-16. nsPs have been shown to have multiple enzymatic functions. For example, papain-like proteases (PLpro) and serine-type Mpro (chymotrypsin-like protease) also called 3CLpro protease, are encoded by nonstructural proteins (nsPs) nsp3 and nsp 5, respectively. This indicates that nsPs play a major role in many molecular processes during host cell invasion, and therefore, have been used for molecular detection of coronaviruses (Anand, Ziebuhr, Wadhwani, Mesters, & Hilgenfeld, 2003; T. Tang, Bidon, Jaimes, Whittaker, & Daniel, 2020) . The next step in the viral replication involves the translation of the sub-genomic RNA into four structural proteins that have been discussed earlier and a variable number of accessory proteins namely 3a, 3b, p6, 7a, 7b, 8b, 9b, and ORF14. The structural proteins undergo post-translational modifications in the endoplasmic reticulum and are then shifted to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) . For viral assembly, once the genome has been replicated, it will interact with the N protein to form a nucleocapsid and relocate into the ERGIC. In this cellular organelle, the nucleocapsid will interact with other structural components to shape vesicles that will eventually be transported out of the cell via exocytosis (Masters, 2006) .

To date, the successful approach that has been found to have concrete ameliorating effects on SARS-CoV-2 infection is plasma therapy. The substantial drug targets of SARS-CoV-2 that have been identified include 3CLpro (Mpro), PLpro, RNA-dependent RNA polymerase, and S proteins (Faheem Kumar et al., 2020; Prajapat et al., 2020) . Irrespective of the impact of the pandemic on healthcare systems, alternate forms of therapy, that is, traditional medicine or their synthetic derivatives have shown some promising results in restricting SARS-CoV-2 viral infection, the most famous being hydroxychloroquine and chloroquine phosphate (Cortegiani, Ingoglia, Ippolito, Giarratano, & Einav, 2020) . Furthermore, numerous other molecules derived from various medicinal plants have been reported to exhibit significant SARS-CoV-2 activities through targeting SARS-CoV-2 activity by meddling with every step of the interaction of the virus with its host cell (Brendler et al., 2020 Yang et al., 2020) , Betulinic acid, Coumaroyltyramine, Cryptotanshinone, Desmethoxyreserpine, Dihomo-γ-linolenic acid, Kaempferol, Lignan, N-cis-feruloyltyramine, Quercetin, Sugiol, Tanshinone IIa (D. H. Zhang, Wu, Zhang, Deng, & Peng, 2020) , hillyraeoidin-E (PR), pseudoheptafuhalol-C (PHF) and a triterpenoidal saponin (GPA) (Khalifa et al., 2020) Zahedipour et al., 2020) ; Propolis, inhibiting TMPRSS2 expression and ACE2 anchorage (Berretta, Silveira, Condor Capcha, & De Jong, 2020; Hori, Zamboni, Carrao, Goldman, & Berretta, 2013; Machado et al., 2012; Pineros et al., 2020) ; Artemisia annua, inhibits pulmonary fibrosis (Haq et al., 2020) ; Tripterygium wilfordii, suppression of TMPRSS2, inhibiting viral entry through the reduction of the spike protein cleavage in ACE2 receptor-mediated viral penetration (Habtemariam et al., 2020; Hoffmann et al., 2020; Ren et al., 2017; Shi et al., 2018) ; Pudilan Xiaoyan Oral Liquid ; and clinically including Glycyrrhiza glabra L. (Cinatl et al., 2003) ; Jinhua

Qinggan granules (H. Chen, Song, Gao, Zhao, & Ma, 2020) ; Xuebijing (Wen, Zhou, Jiang, & Huang, 2020) . This review is intended to deliver cumulative pieces of information regarding the natural compounds or their derivatives that have shown potential preventive as well as therapeutic effects on SARS-CoV-2 either in silico, in vitro, in vivo, and or clinically.

During the first SARS-CoV pandemic, patients with SARS who were treated with Traditional Chinese Medicines (TCM) had a short- .

Pulmonary fibrosis that has been identified as one of the primary SARS-CoV-2 sequelae, leads to a deterioration of the lungs along with dyspnea. Furthermore, it has a life-threatening impact on patients leading to poor prognosis and high mortality, and poor prognosis. Vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) regulate the molecular pathway of pulmonary fibrosis and Chinese herbal preparations have shown a strong therapeutic effect on pulmonary fibrosis. The therapeutics modulation of pulmonary fibrosis by TCM was explored by screening the candidates for VEGFR and FGFR inhibition. The docking analysis of VEGFR and FGFR was set up to obtain the potential active ingredients, which were filtered by the docking score. The candidates for treating pulmonary fibrosis mostly belonged to the lung and spleen. Therefore, Qiyin 

Amid well-described coronaviruses, Mpro has been described as a top drug target. Indeed, the numerous cleavage sites fragmented by Mpro (11 sites (Basu et al., 2020) . Quercetin a flavonol that belongs to flavonoid compounds is derived from quercetum (oak forest) known for its antiinflammatory and antiviral properties, is an FDA-approved compound as part of antioxidant and anti-allergy medicines (Fischer, Speth, Fleig-Eberenz, & Neuhaus, 1997) . Coronil, an herbal formulation of Tinospora cordifolia, Withania somnifera, and Ocimum sanctum was reported to suppress the SARS-CoV-2 S-protein dependent entry of the virus in A549 cells by inhibiting the interaction of spike protein with ACE-2 ( Figure 2) . Coronil was reported to regulate the levels of IL-6, IL-1β, and TNF-α in A549 cells (Balkrishna, Haldar, Singh, Roy, & Varshney, 2021 

Pulmonary fibrosis is seen in SARS-CoV-2 infection with advanced gravity (Ojo, Balogun, Williams, & Ojo, 2020) . Numerous findings suggest that pulmonary diseases are correlated with oxidative stress, therefore, the consumption of antioxidant compounds from natural products is effective in lung fibrosis (Day, 2008) . Artemisia annua L. is used in both the Asian and African continent in a form of tea or press juice for the treatment of malaria and associated fever, chills, and its well-known active compound Artemisinin (ARS), is now used all over the world as an antimalarial drug but also to target hepatitis B virus, 

Celastrol (tripterine), a phytochemical extracted from the roots of Tripterygium wilfordii (Thunder god vine) has been widely investigated, for its antiinflammatory as well as anticancer potential, which is believed to be mainly modulated through its ability to inhibit the production of cytokines and chemokines that could conduct to the suppression of leukocyte migration into the inflamed joints, leading to antiinflammatory activity. Celastrol has also shown promising 

Glycyrrhiza species (licorice) have displayed antiviral effects against numerous viral infections (Brendler et al., 2020; Fiore et al., 2008) .

Cinatl et al. have tested ribavirin, 6-azauridine, pyrazofurin, mycophenolic acid, and glycyrrhizin, which are saponin derivatives discovered in licorice roots of Glycyrrhiza glabra L., Fabaceae toward two clinical samples of SARS-CoV (one from Frankfurt patients and the second from Hong Kong). They have been shown to successfully inhibit the adsorption, entrance, and replication of SARS-CoV-2 in its host cells (Cinatl et al., 2003) . Saikosaponin B2 has also been proved to have a strong activity as an inhibitor of virus-host cell binding and entrance modulating the early stage of SARS-CoV-2 replication (Cheng et al., 2006) . 

Xuanfei Baidu Tang (XFBD) is a herbal compound that has been Flos combined with Morus alba L. when taken with modern medicine, symptomatic supportive treatment for SARS-CoV-2 has shown significantly better effects than symptomatic supportive therapy alone .

Jinhua Qinggan granule (JHQGG) is a Chinese multi-herbal formula that has been first developed as a medicine for H1N1 influenza and has been highly suggested for suspicious clinical cases of SARS-CoV-2, indeed JHQGG has been shown to shorten the timing of viral nucleic acid detectability and a quick viral clearance rate, in addition to speed the pneumonia recovery time of the treated SARS-CoV-2 patients, all that without adverse reactions .

Xuebijing ( 

A study led by Derosa et al. has shown that Quercetin, a flavonol that belongs to flavonoid compounds is derived from quercetum (oak forest) known for its antiinflammatory and antiviral properties could suppress SARS-CoV-2 cell entry, replication, and inhibit 3CLpro and PLpro in vitro (Abian et al., 2020; Derosa et al., 2021; Gentile et al., 2020) . Hence, Quercetin is currently undergoing several clinical trials [NCT04578158, NCT04377789, NCT04468139, and NCT04622865] as anti-SARS-CoV-2 candidate (Abian et al., 2020; Islam et al., 2020) .

The multi-targeting anti-viruses power of curcumin arises from its faculty to interfere with numerous molecular pathways hence initiating cellular signaling pathways involved in pulmonary disease, metabolic diseases, liver diseases, and inflammation (Brendler et al., 2020) . (Pourhajibagher et al., 2021) . In addition, it has been demonstrated that curcumin treatment can modulate the structure of the S protein in viruses, and hence block the viruses' entry into the cells (T. Y. Chen et al., 2013) . Using molecular docking, curcumin was shown to bind to RBD-S, PD-ACE2, and SARS-CoV-2 protease (Soni et al., 2020; Zahedipour et al., 2020) .

In Vero E6 cells, PDL with an EC50 = 1.078 mg/ml has been observed to effectively suppress the viral duplication of SARS-CoV-2, suggesting that virus infection was vigorously blocked by PDL .

In human fetal lung fibroblasts, Saikosaponins A, B2, C, and D were tested against SARS-CoV-2. No cytotoxicity has been detected with saikosaponins A, B2, C, and D up to a concentration of 25 μmol/L, where, identically, all the compounds have shown a strong SARS-CoV-2 inhibition. The highest efficiency has been observed with saikosaponin B2 leading to 100 ± 0.2% of inhibition at 25 μmol/L.

EC50 values for saikosaponins A, B2, C, and D were defined to be 8.6 ± 0.3 (SI = 26.6), 1.7, 19.9, and 13.2, respectively. Additional investigations have been led and have confirmed that saikosaponin B2 had the strongest activity as a virus-host cell attachment and penetration inhibition (Cheng et al., 2006) .

Propolis, a resinous material produced by honey bees from plant exudates, has long been used in traditional herbal medicine and is widely consumed as a health aid and immune system booster. There is considerable evidence that propolis can reduce and alleviate the symptoms of inflammatory diseases by affecting various metabolic cycles. Recently, several studies have shown that propolis extract and some of its components act against several important targets of SARS-CoV-2, such as reducing TMPRSS2 expression, and reducing ACE2 anchorage; this is in addition to immuno-modulation of monocytes/macrophages (reducing the production of and eliminating IL-1 beta and IL-6), reduction of the transcription factors NF-KB and JAK2/STAT3 and blocking PAK1, which determine inflammatory activities and fibrosis caused by SARS-CoV-2 (Berretta et al., 2020; Hori et al., 2013; Machado et al., 2012; Pineros et al., 2020) .

Pulmonary fibrosis, found in SARS-CoV-2 infected people is proved to be mediated by Interleukin-1 (IL-I) induction that occurs after virus binding to TLR. IL-I is a pleiotropic cytokine, highly inflammatory, the mediator of fever, and fibrosis. HSP47 is associated with collagen accumulation along with TGF-β1 and its downstream molecules Smad3 and α-SMA; which are up-regulated in pulmonary fibrosis. In rats, Artemisia annua has been shown to inhibit all the cited molecules and their corresponding pathways, which inhibits pulmonary fibrosis and there may be used as a possible treatment for SARS-CoV 2 (Haq et al., 2020). (Habtemariam et al., 2020) . Moreover, celastrol has shown promising results in reducing chronic obstructive pulmonary disease in mice via antiinflammatory mechanisms, including the reduction of the levels of the inflammatory cytokine such as IL-8, TNF-α, and monocyte chemoattractant protein-1 while increasing the antioxidant defenses that includes superoxide dismutase and catalase (Shi et al., 2018) . In patients suffering from asthma or with enhanced airway hyper-responsiveness, a positive outcome for orally administered celastrol both in the disease level and Th17 proinflammatory cells suppression was observed in vivo (Zeng, Lin, Zheng, Zhang, & Zhang, 2018) whereas, under ventilator-induced lung injury in mice, celastrol was shown to ameliorate the outcome (Ren et al., 2017) .

In transgenic mice, SARS-CoV-2-infected hACE2, dispensed by intragastric route with PDL (4 ml/kg) from 1 hour post virus inoculation, then once daily for 5 days, has been shown to reduce the viral RNA copies in the lungs in SARS-CoV-2-infected hACE2 mice with PDL treatment in comparison with the model control group.

In SARS-CoV-2-infected hACE2 mice, lung tissues at 5 dpi had restrained pneumonia with interstitial hyperplasia. Furthermore, the alveolar interstitium was thickened with inflammatory cells, inflammatory cells and infiltration around blood vessels were observed. In comparison, the lung tissues from PDL-treated mice displayed mild interstitial pneumonia along with limited amounts of inflammatory cells infiltrated, even though the alveolar interstitium expanded .

6 | NATURAL COMPOUNDS FOR ORGANS PROTECTION 6.1 | Liver and kidney injury

Post-infection by SARS-CoV-2, an enhanced incidence of acute kidney injury is observed, which is most probably due to the presence of the virus, the inflammatory response, or a synergistic impact of both these factors on kidneys. It has been demonstrated that patients with acute renal injury have a higher mortality rate. ACE2 is strongly expressed in the kidneys (Mizuiri & Ohashi, 2015; Toapanta et al., 2021) . A decrease in ACE2 and an enhancement in ACE expression might eventually lead to renal damage in diabetes (Mizuiri & Ohashi, 2015) . 

ACE2 plays a key role in cardiovascular function as well as in the development of diabetes and hypertension (Turner, Hiscox, & Hooper, 2004) . SARS-CoV-2 infectious process starts by the binding of the virus spike protein to ACE2 receptors, which are vastly expressed in different organs such as the heart, lungs, and kidney. As a result, SARS-CoV-2 leads to respiratory syndrome through its entrance to the alveolar epithelial cells. It has been determined that these syndromes are more prominent in subjects with cardiovascular disease, which might be due to their highest ACE2 display. Given that ACE2 operates as a receptor for SARS-CoV-2, the safety and potential effects of anti-hypertension therapy with angiotensin-receptor blockers or ACE inhibitors in SARS-CoV-2 clinical cases might be investigated (Mourad & Levy, 2020; Zheng, Ma, Zhang, & Xie, 2020) .

Nevertheless, the decrease of ACE2 activity is injurious to the heart, since it contributes to cardiac dysfunction, which is due to a higher stimulation of the AT1 receptor by angiotensin II (Gheblawi et al., 2020; Mourad & Levy, 2020; Zheng et al., 2020) . In this context, it has been shown that curcumin considerably lowers mean arterial blood pressure and ameliorates cardiac fibrosis in vivo by upregulating angiotensin type II receptor, down-regulated angiotensin II type I receptor, and increasing ACE2 in the myocardium without notable harmful side effects (Pang et al., 2015) . the replicative process at its initial stage, but also the adsorption, and penetration of the virus in its host cells (SI of 67). Notably, it has also been highlighted that its effect was more limited when added during the virus adsorption (EC50 = 600 mg/L), whereas it had the highest inhibition when added after the virus adsorption (EC50 = 300 mg/L, 364.5 μM). Moreover, a dose of 1,000 mg/L glycyrrhizin treatment resulted in a lower viral antigen expression. The authors have also determined that the glycyrrhizin mechanism of action was likely the induction of nitric oxide synthase (Cinatl et al., 2003 amelioration between the two groups was compared. The average time of viral nucleic acid detection was (7 ± 4) days in the Jinhua Qinggan administration group, in which 56.82% of the patients had negative nucleic acid tests within 7 days or less versus (10 ± 4) days for the control group with a significantly higher viral clearance rate for the Jinhua Qinggan group compared with the control one. Furthermore, the pneumonia recovery time indicated by chest CT was (8 ± 4) days in the Jinhua Qinggan group, versus (10 ± 5) days for the control ).

In Changsha hospital, china, sixty severe SARS-CoV-2 patients were admitted from January to March 2020 and had been randomly distributed into three groups of 20 cases each, the first group has been treated with a routine treatment (Treatment according to the national health commission protocol), the second one with Xuebijing 50 m that was injected two times a day for 7 days, and the last one with Xuebijing 100 ml also through injection twice a day for 7 days. The blood routine test, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), acute physiology and chronic health evaluation II (APACHE II) score, SARS-CoV-2 nucleic acid test, and disease classification of the patients before treatment versus after the treatment protocol was observed. Post-treatment, the white blood cell count (WBC) and lymphocyte count (LYM) of all the groups increased, whereas CRP and ESR decreased. In comparison with Xuebijing 50 ml group, the increase of WBC, and the decrease of CRP and ESR were more significant in Xuebijing 100 ml group. Interestingly, post-Xuebijing treatment, the APACHE II score decreased more significantly in the Xuebijing treated groups in a dose-dependent manner compared to the routine group. In addition, post-treatment the SARS-CoV-2 nucleic acid test to some extent turned negative, with nine cases in the routine treatment group, eight cases in Xuebijing 50 ml group, and nine cases in Xuebijing 100 ml group, without significant difference. Overall, the patients with the best recovery and better scores were those treated with Xuebijing 100 ml (Wen et al., 2020) .

Naturally occurring phytochemicals offer excellent resources for drug design and conception. Additional chemical modulations of these compounds, oriented by computer-based docking simulations, might also strengthen their effectiveness and/or selectivity. Among the main promising products for the treatment of SARS-CoV-2 in humans that have been discussed in this review Curcuma longa, Artemisia annua L., Tripterygium wilfordii, Saponin derivates, PDL, XFBD, Lonicerae Japonicae Flos and Morus alba L., JHQGGs, and Xuebijing. Nevertheless, these compounds may have adverse or toxic effects at certain concentrations, and therefore, further investigations are necessary to define safe therapeutic doses for each compound before its clinical application. Preliminary studies could investigate the products that have formerly been approved for drug use or are generally considered to be safe by drug regulating agencies and administrations. Finally, it is hoped that the scientific community will continue to develop safe, and effective anti-SARS-CoV-2 therapeutic agents from naturally derived compounds.

The authors declare no conflict of interest.

None.

https://orcid.org/0000-0002-3492-2957

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Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression

Coronavirus membrane fusion mechanism offers a potential target for antiviral development

Kidney transplantation and COVID-19 renal and patient prognosis

ACE2: from vasopeptidase to SARS virus receptor

Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein

Mechanism of Xuanfei Baidu Tang in treatment of COVID-19 based on network pharmacology

Site-specific glycan analysis of the SARS-CoV-2 spike

Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus

Effect of Xuebijing injection on inflammatory markers and disease outcome of coronavirus disease 2019

A new coronavirus associated with human respiratory disease in China

Food as medicine: A possible preventive measure against coronavirus disease (COVID-19)

Potential effects of curcumin in the treatment of COVID-19 infection

Celastrol alleviates airway hyperresponsiveness and inhibits Th17 responses in obese asthmatic mice

In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors

Celastrol attenuates renal injury in diabetic rats via MAPK/NF-kappaB pathway

COVID-19 and the cardiovascular system

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Natural products and phytochemicals as potential anti-SARS-CoV-2 drugs