key: cord-0867139-4cmnv6us
authors: Ospanov, Meirambek.; Leó, Francisco; Janar, Jenis; Khan, IKhlas A.; Ibrahim, Mohamed A.
title: Challenges and future directions of potential natural products leads against 2019-nCoV outbreak
date: 2020-10-08
journal: Curr Plant Biol
DOI: 10.1016/j.cpb.2020.100180
sha: 6cba8235805896bdb7d392c339980d9d39e4fab3
doc_id: 867139
cord_uid: 4cmnv6us

Except for Remdesivir® no other drug or vaccine has yet been approved to treat the coronavirus disease (COVID-19) caused by the virus known as, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir® an small molecule and nucleic acid analogue, it is used to treat adults and children with laboratory confirmed COVID-19, only administrated in hospital settings. Small molecules and particularly natural products count for almost fifty percent of the commercially available drugs, several of them are marketed antiviral agents and those can be a potential agent to treat COVID-19 infections. This short review rationalized different key natural products with known activity against coronaviruses as potential leads against COVID-19.

Coronaviruses (CoVs) are the largest group of viruses belonging to the Nidovirales order, which includes Coronaviridae, Arteriviridae, and Roniviridae families. The Coronavirinae comprises one of two subfamilies in the Coronaviridae family, with the other being the Torovirinae [1] . Coronaviruses are named for the crown-like spikes on their surface and there are four main sub-groupings of coronaviruses, known as alpha, beta, gamma, and delta [2] . Human coronaviruses were first identified in the mid-1960's [3] . Coronaviruses cause acute and chronic respiratory, enteric and/or central nervous system diseases in many species, including humans [4] .

There are seven coronaviruses that can infect human worldwide, four common types are 229E and NL63 (alpha coronavirus), while OC43 and HKU1 (beta coronavirus). Sometimes animal coronaviruses can cross-species transmitted and infect humans [5] . [7] .

Currently, it is difficult to generate animal models capable to simulate the key features for the human disease. These models are aiming to find the pathogenic mechanism, search for avenues to identify targets on the virus suitable for attack and design successful treatments.

Natural compounds are potential sources for the development of antiviral agents. Various medicinal herbs producing anti-inflammatory, antifungal, and antitumor activities have been extensively studied in order to identify the herbs possessing antiviral properties. Indeed, chloroquine, the first small molecule Food and Drug Administration (FDA) approved to treat COVID-19, later revoked, was inspired and developed from quinine sharing the same quinoline core (Fig. 1) . Quinine is the bioactive component, an old antimalarial agent, it was isolated from the bark of Cinchona officinalis used for centuries by the Inca empire in South America to treat malaria and other illness [14] . Remdesivir® possessed broad activity against RNA viruses; many research groups assessed its antiviral activity both in vitro and in vivo, validating its activity against coronaviruses. Its antiviral activity was confirmed against SARS, MERS zoonotic coronaviruses, as well as the circulating human coronaviruses HCoV-OC43 and HCoV-229E, which cause common human cold. In vitro and preclinical in vivo animal models supported the effectiveness of Remdesivir® against SARS-CoV-2 and related coronaviruses. These include a recent in vitro study of Remdesivir® assessing antiviral activity against SARS-CoV-2 using qRT-PCR J o u r n a l P r e -p r o o f quantification of viral copy number in infected Vero E6 cells. This study demonstrated an IC50 of 770 nM and an IC90 equal to 1,760 nM (with cytotoxic concentration >100 mM). The mechanism of action of Remdesivir® is attacking a weak point of viral replication within the host, such as targeting the divergent RNA-dependent RNA polymerase (RdRp). The chemical structure for Remdesivir® resembles adenosine one (Fig. 2) . Imagining under cryo-electron microscopy confirm Remdesivir® latches onto the primer RNA of the virus shutting down the viral reproduction [15] .

Recently, Y. Wang et al. reported randomized, double-blind, placebo-controlled trial in hospitalized adults with severe COVID-19 in China. Adverse effects such as constipation, hypoalbuminemia, hypokalemia, anemia, and thrombocytopenia as well as increased total bilirubin concentrations were reported in 66% of patients who received Remdesivir®. Serious adverse events reported in 18%, and drug discontinued because of the adverse events [16] . Next section is a compilation of the natural products that have been shown to be active against the coronavirus affecting the human health. The compounds are grouped according to their biosynthetically origin.

Several alkaloids have shown antiviral activity, for example, Kim et al. 2019 , showed that bis-benzylisoquinoline alkaloids such as, tetrandrine (1), fangchinoline (2), and cepharanthine [17] . Tetrandrine (1) and fangchinoline (2) showed in vitro antiviral activity against human coronavirus [18] . The expression levels of the Sand N-proteins in MRC-5 lung human cells infected with HCoV-OC43 at two days' postinfection were significantly diminished and virus replication was suppressed by the action of alkaloids 1-3. These alkaloids did not show cytotoxic effects on MRC-5 cells up to 10 μM (CC50 > 10 μM). The IC 50 values of tetrandrine (1), fangchinoline (2), and cepharanthine (3) were 0.33 ± 0.03, 1.01 ± 0.07, and 0.83 ± 0.07 μM, respectively [19] . This in turn demonstrated that tetrandrine (1), fangchinoline (2), and cepharanthine (3) inhibited HCoV-OC43 at the early stage of infection which is mainly due to suppression of the replication of HCoV-OC43 virus [19] .

Tetrandrine (1) has been known as antagonist of calmodulin, has anti-tumor, antiinflammatory effects, and can effectively inhibit fibroblasts and thereby inhibiting pulmonary J o u r n a l P r e -p r o o f fibrosis [20] . Since the 1950s, tetrandrine (1) has been used in China as an antihypertensive drug.

In 1970s, tetrandrine (1) underwent a phase I clinical trial as an antitumor drug in US. Although tetrandrine is not in clinical use in countries other than mainland China, it has been used in research worldwide showing to have multiple pharmacological activities including immunosuppression, antihypertensive, and antitumor activities. Tetrandrine had a synergistic effect on the cytotoxicity of the chemotherapeutic agents; 5-fluorouracil, oxaliplatin, and docetaxel in two gastric cancer cell lines [21] . Fangchinoline (2) is known to have inhibitory effects on histamine release and on the production of IL-1 and tumor necrosis factor-a (TNF-α).

Also, fangchinoline was identified as capable of inhibiting PI3K and its downstream signaling pathways and suppressing PI3K-mediated SGC7901 behavior including growth, migration, and invasion. Further testing in experimental models in vivo is warranted [22] .

In an extensive study, more than 200 Chinese medicinal herb extracts were screened for antiviral activities against (SARS-CoV) using 3-(4,5-dimethylthiazol-2-yl)-5-(3carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay for virusinduced cytopathic effect (CPE) [19] . The extracts of Lycoris radiata, Artemisia annua, Pyrrosia lingua, and Lindera aggregata showed potent antiviral activities against SARS-CoV strain BJ001 with 50% effective concentration (EC50) 2.4 ± 0.2, 34.5 ± 2.6, 43.2 ± 14.1, and 88.2 ± 7.7 g/mL, respectively. Among those extracts, L. radiata extract showed the best inhibition effect in SARS-CoV bioassay guided fractionation yielded lycorine (4) as the main bioactive components (Fig. 3) . The EC50 value for lycorine (4) was found to be 15.7 ± 1.2 nM. The CC50 of lycorine (4) in Vero E6 and HepG2 cells were 14980.0 ± 912.0 and 18810.0 ± 1322.0 nM, respectively [23] . Lycorine (4) can cause toxic effects at low doses in canines' model (around 1 J o u r n a l P r e -p r o o f mg/kg), further development of this compound as a potential drug candidate is needed, and the mechanism of its antiviral activity is still not clear [24] .

Isatis indigotica root is a Chinese herb frequently used for the prevention of SARS during the SARS outbreaks in China, Hong Kong, and Taiwan. The main components of I. indigotica root are the alkaloids; indigo (5), indirubin (6) , and indican (indoxyl-β-D-glucoside) (7) , and the allyl glucosinate, sinigrin (8) (Fig. 3) . Indigo (5) and indirubin (6) were identified as the promiscuous chymotrypsin inhibitors [25] . C.W. Lin et al. [26] characterized the anti-SARS-CoV 3CL pro effect of the water extract of I. indigotica root-derived compounds. Of the five compounds that were tested in vitro, sinigrin (8) and indigo (5) Brassicaceae family, such as broccoli and Brussels sprouts. In seeds of Brassica nigra (mustard seeds) sinigrin (8) is found in high concentration, mustard has been used for centuries by mankind for its culinary, as well as various medicinal properties [27] . The expression of nucleocapsid (N) protein essential for MERS-CoV replication was decreased after resveratrol treatment, down regulating the apoptosis induced by MERS-CoV in vitro assay [28] . Resveratrol also has been found to inhibit herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) replication in a dose-dependent, and reversible manner [29] . In several toxicity studies, resveratrol was orally administrated at its maximum tolerated doses to access its J o u r n a l P r e -p r o o f adverse effects; the results show the lack of carcinogenicity. Reports revealed the absence of acute skin and eye irritation or other allergenicity signs that could be caused by the compound.

Despite being an estrogen-like compound, studies provide further evidence that trans-resveratrol has low estrogenic potency in vivo [30] . A large amount of resveratrol is produced in the skin of grapes to protect the plant against fungal diseases and sun damage [31] . Resveratrol is widely available on red wine extract, grape seed extract, and Japanese knotweed extract and others.

Most supplements on the market are derived from Japanese knotweed as it has the highest concentrations of resveratrol in nature [32] . Commercial dietary supplements contain an average between 50 to 500 mg of trans-resveratrol (11), human clinical studies have also been performed up to single doses of 5 g of resveratrol without observing adverse effects [30] . These data suggest that trans-resveratrol (11) is well tolerated in humans and that 450 mg/day can represent a safe dose for a 70 kg individual [33] . Resveratrol has low systemic bioavailability and is available in solution form and as a transdermal patch, however, its safety and effectiveness have not been approved by the FDA [34] .

Amentoflavone (12) a bi-flavonoid isolated from Selaginella sinensis, Torreya nucifera, and other medicinal plants has shown in vitro potent antiviral activity against respiratory syncytial virus (RSV), with an IC 50 of 5.5 g/mL [35] , as well as significant activity against influenza A and B viruses [36] . Additionally, amentoflavone (12) revealed moderate anti-herpes simplex virus HSV-1 and anti-HSV-2 activities with EC50 values of 17.9 g/mL (HSV-1) and 48 .0 g/mL (HSV-2), and also described as SARS-CoV 3CL protease inhibitor, an IC50 is 8.3

µM [37] . This compound has shown high cytotoxicity against MCF-7 and HeLa cancer cell lines [38] . [39] . It has been noticed that neither myricetin (13) nor scutellarein (14) can affect the growth of MCF10A cells at cellular concentrations close to their IC50's [40] .

Myricetin (13) is a typical plant-derived flavonoid produced fundamentally by individuals from the families Myricaceae, Anacardiaceae, Polygonaceae, Pinaceae, and Primulaceae and considered as one of the key elements of different beverages [40] .

Myricetin (13) shows a wide spectrum of activities that incorporate anti-oxidant, anticancer, antidiabetic and anti-inflammatory activities [41] . It shows a few activities that are identified with the central nervous system (CNS) and the compound suggested to be useful against Parkinson's and Alzheimer's diseases [42] . According to some reports myricetin (13) has the capability to modify the immune response or functioning of the immune system [42] . This compound has cytotoxic and apoptosis-promoting effects in PCa cells [43] .

Scutellaria baicalensis roots have been widely used in traditional Chinese medicine to treat viral infection [44] . In vitro and in vivo replication of SARS-CoV can be inhibited by the flavonoid Baicalin (15) , which is isolated from S. baicalensis. Numerous inhibitory activities were confirmed for baicalin (EC50 at 48 hrs is 12.5 to 25 µg/mL and at 72 hrs is 25 to 50 µg/mL) by virtue of neutralization-based testing of the other nine SARS coronavirus isolates [45] . . Baicalin has been shown to possess potential cytotoxicity [47] .

Tannic acid (19) (IC 50 = 3 µM) and 3-isotheaflavin-3-gallate (20) (IC 50 = 7 µM) (Fig. 5) were shown to be potent inhibitors of SARS 3CL pro by virtue of high-throughput screening of a natural product library (approx. 720 compounds) [48] . These two compounds pertain to a group of natural polyphenols found in tea [45] . According to the results obtained, the extracts from Puerh tea and black tea were the most potent inhibitors of SARS protease activity [48] . It was also reported that bovine coronavirus and rotavirus infections could be neutralized by theaflavins extracted from black tea [49] with EC50 of 34.7 µg/mL. The findings also corroborate the presence of an inactivation activity (in vitro) of theaflavin and theaflavin gallate derivatives (20) against both rotavirus and coronavirus. Many polyphenols were discovered to be more potent as inhibitors of papain-like protease (PL pro ) than those of 3-chymotripsin-like protease (3CL pro ) [50] . Among these polyphenols, papyriflavonol (22) (Fig. 6 ) was discovered to manifest the most potent inhibitory activity against PL pro with an IC50 value of 3.7 µM while C5-alkyl group (prenyl)-substituted flavan (23) was the most potent against SARS-CoV 3CL pro which was proven to be more effective than quercetin derivative (IC50 = 52.7 µM).

proteases associated with viral replication is due to their protein affinity via hydrogen bonding [51] .

folk medicine in a number of Asian countries. It is effective in the treatment of pneumonia, infectious diseases, refractory hemoptysis, and malignant pleural effusion [52] . It was the main herbal component of heat-removing and detoxifying formula during the severe acute respiratory syndrome (SARS) outbreak in 2002 -2003 [53] . Considerable inhibitory effects were demonstrated in vitro and in vivo by HC water extract on both SARS-CoV 3C-like protease (3CL pro ) and RNA-dependent RNA polymerase [54] , where HC extract was discovered to be an effective inhibitor of [α-32 P] UTP incorporation at 50 µg/mL. Interestingly, oral acute toxicity analysis demonstrated that HC was non-toxic to laboratory animals after an oral administration at 16 g/kg.

The inhibitory activities of chalcones and coumarins isolated from the edible Angelica keiskei against SARS-CoV proteases (3CL pro and PL pro ) were determined (cell-free/based) [55] .

Xanthoangelol E (24) (Fig. 6) , exhibited the most inhibitory activity against 3CL pro and PL pro with IC50 values of 11.4 and 1.2 M [56] . Data suggested that chalcones exhibited competitive inhibition to the SARS-CoV 3 CL pro and noncompetitive inhibition to the SARS-CoV PL pro . triterpenoids and one flavonoid glycoside [57] . The antiviral activity of all isolated compounds was evaluated. The assay results indicated the highly influence of the antiviral activity with small differences in the structural features of the tested compounds. Among the friedelane derivatives tested, the two epimers, 3β-friedelanol and 3α-friedelanol, with difference in orientation at C-3 that affected dramatically their antiviral activity while epitaraxerol (25) (Fig. 7) , a taraxerane derivative, was the most active derivative. (Fig. 7) , the active component of liquorice roots, has been reported to possess moderate antiviral activity against SARS-CoV in vitro with an EC50 of 300 g/mL [58] , however its full mechanism is unclear. Glycyrrhizin affects cellular signaling pathways such as protein kinase C; casein kinase II; and transcription factors such as activator protein 1 and nuclear factor kB. where Saikosaponin B2 (27) (Fig. 7) has potent anticoronaviral activity [62] . The percentage viral inhibition for 0.25, 2.5, and 25 µmol/L Saikosaponin B2 was 35.7 ± 0.7, 63.0 ± 0.8, and 100.0 ± 0.2%, respectively. The mechanistic studies show that Saikosaponin B2 inhibits HCoV-229E infection in a dose-and time-dependent manner, block viral penetration into cells, and interfere with the early stage of viral replication, such as virus absorption and penetration.

In another study, 221 phytocompounds were evaluated for their activity against Severe Acute Respiratory Syndrome associated coronavirus (SARS-CoV) using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Twenty tested compounds exhibited significant levels of anti-SARS-CoV activity at 10 μM with no cytotoxicity against Vero E6 cells. Due to its pivotal role in the SARS-CoV life cycle, the 3CL protease is a key target for discovery of anti-SARS-CoV agents [63] . The inhibitory effects of compounds on SARS-CoV 3CL protease activity were investigated. Only betulinic acid (28) (IC50 = 10 μM, Ki = 8.2  0.7 μM) and savinin (29) (IC50 = 25 μM, Ki = 9.1  2.4 μM) (Fig. 7 ) exhibited significant inhibition on 3CL protease. The mechanism of action of betulinic acid and savinin on 3CL protease was shown to be competitive inhibition via molecular docking [63, 64] .

Alnus japonica and its constituents exhibit various biological properties, including antiinflammatory, anticancer, and anti-influenza activities. The ethanol extract of the stem bark of A. japonica exhibited PL pro inhibitory activity. Nine diarylheptanoids were identified; platyphyllenone, hirsutenone (30), platyphyllone, platyphyllonol-5-xylopyranoside, hirsutanonol, oregonin, rubranol, rubranoside B (31) , and rubranoside (32) (Fig. 8 ) [65] . The isolated 

The diarylheptanoids were found to be reversible inhibitors, where an increase in concentration rapidly reduced enzyme activity [65] . Structural Activity Relationship (SAR) of diarylheptanoids established that α, β-unsaturated carbonyl and catechol groups may play a pivotal role in SARS-CoV PL pro inhibition by interacting with the PL pro nucleophiles [65] . The mechanism of inhibition of cysteine protease may involve the formation of a covalent bond between the carbonyl group located at the warhead of the inhibitor and the cysteine active site residue in the enzyme. Ho et al. [66] . The herbs were divided by the team into 32 families in order to compare the levels Polygonaceae [67] . Emodin, the major components of the genus Rheum and Polygonum, is the likely active constituent responsible for blocking both the binding of SARS-CoV S protein to ACE2. Emodin (33) (Fig. 9 ) blocked the binding of S protein to ACE2 in a dose-dependent manner. The IC50 value of emodin is 200 M. Emodin is an anthraquinone compound consists of three cyclic rings. The anti-psychotic drug promazine (34) (Fig. 9) , which has been shown to exhibit the significant effect in inhibiting the replication of SARS-CoV [68] , shared a similar structure with emodin. As compared to emodin, promazine exhibited the highest inhibition.

However, the differences between emodin and promazine were not significant. 

Many anti-immune treatments, investigational clinical trials using repurposed drugs for evaluation of direct antiviral activity have already been launched, including multiple antiviral and antimalarial medicines [68] . A great effort has been addressed towards sharing information on biomolecular simulation data to reveal models of how the coronavirus could potentially infect human, as well as how to prevent and/or treat COVID-19 [69] . Desferrioxamine B (Desferal®) is produced by Streptomyces pilosus and the only siderophore currently marketed (DB00746). It is produced by the fermentation of S. pilosus and is used therapeutically in patients with iron and aluminum overload [79] . Desferrioxamine B is J o u r n a l P r e -p r o o f also known for its antiproliferative activity against leukemia and neuroblastoma cells in vitro and in vivo and in current clinical trials for its antitumor activity [80] . Replication of human immunodeficiency virus type 1 (HIV-1) can be influenced by iron, hence, decreasing the availability of iron may inhibit HIV-1 replication, where deferoxamine is capable of forming catalytically inactive iron-chelator complexes [81] .

J o u r n a l P r e -p r o o f Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamid, Avigan®) is an antiviral drug that selectively inhibited the RdRP of influenza virus [83] . It showed specific activity against all three influenza A, B, and C [84, 85] . The primary mechanism of action of favipiravir against the influenza virus was through specific inhibition to vRNA polymerase [86] . Favipiravir functions as a purine homologue, where vRNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide resulted in inhibition of viral RNA synthesis [86] .

Colchicine (Colcrys®) is an alkaloid isolated from the plant Colchicum autumnale. It is a drug used to treat gout and Behçet's disease with narrow therapeutic-toxicity window and a marked variability between individuals in drug disposition [87] . Colchicine binds in an equimolar and poorly reversible manner to soluble nonpolymerized tubulin with high activation energy, forming a tubulin-colchicine complex [88] .

J o u r n a l P r e -p r o o f It appears through this short review that natural products with the unique pharmacophores and high safety margin will present key element in dealing with the pandemic 2019-nCoV.

There is an urgent and critical need to identify novel medical countermeasures both for prophylactic and treatment use. Since the production of a vaccine could take 12-18 months, and de novo development of therapies usually requires 10-17 years, repositioning clinically evaluated drugs represents one of the most practicable strategies for the rapid identification and deployment of treatments for emerging infectious diseases such as COVID-19 [65] .

Conflict of interest, the authors declare no conflict of interest.

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