Screening for natural and derived bio-active compounds in preclinical and clinical studies: One of the frontlines of fighting the coronaviruses pandemic

Abstract

Background

Starting December 2019, mankind faced an unprecedented enemy, the COVID-19 virus. The world convened in international efforts, experiences and technologies in order to fight the emerging pandemic. Isolation, hygiene measure, diagnosis, and treatment are the most efficient ways of prevention and intervention nowadays. The health organizations and global care systems screened the available resources and offered recommendations of approved and proposed medications. However, the search for a specific selective therapy or vaccine against COVID-19 remains a challenge.

Methods

A literature search was performed for the screening of natural and derived bio-active compounds which showed potent antiviral activity against coronaviruses using published articles, patents, clinical trials website (https://clinicaltrials.gov/) and web databases (PubMed, SCI Finder, Science Direct, and Google Scholar).

Results

Through the screening for natural products with antiviral activities against different types of the human coronavirus, extracts of Lycoris radiata (L'Hér.), Gentiana scabra Bunge, Dioscorea batatas Decne., Cassia tora L., Taxillus chinensis (DC.), Cibotium barometz L. and Echinacea purpurea L. showed a promising effect against SARS-CoV. Out of the listed compound Lycorine, emetine dihydrochloride hydrate, pristimerin, harmine, conessine, berbamine, 4`-hydroxychalcone, papaverine, mycophenolic acid, mycophenolate mofetil, monensin sodium, cycloheximide, oligomycin and valinomycin show potent activity against human coronaviruses. Additionally, it is worth noting that some compounds have already moved into clinical trials for their activity against COVID-19 including fingolimod, methylprednisolone, chloroquine, tetrandrine and tocilizumab.

Conclusion

Natural compounds and their derivatives could be used for developing potent therapeutics with significant activity against SARS-COV-2, providing a promising frontline in the fighting against COVID-19.

Graphical abstract

Introduction

Coronaviruses were isolated in 1965 from the respiratory tract of adult humans with common cold symptoms (Kahn and McIntosh, 2005). At the beginning, the endemic corona viruses such as: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 caused mild upper respiratory disease in humans (Chan and Chan, 2013). In the past two decades coronaviruses have appeared on a large pandemic scale displayed by the appearance of the severe acute respiratory syndrome virus (SARS-CoV) followed by the other types of Coronaviruses like (MERS-CoV) (Chan-Yeung and Xu, 2003). The severe respiratory syndrome virus reached many countries and affected many people after crossover from animal (bats as a natural reservoir host) to human, causing high fatality rates (Yuan et al., 2017). The novel SARS-CoV-2 belongs to the coronavirus family that appears to have originated from bats with unknown intermediate host (s) (Deng et al., 2020).

Nowadays, the incidence and spread of the new coronavirus disease 2019 (COVID-19) in Wuhan City, Hubei province in China became a threat to the world and a recent public health crisis (Singhal, 2020). On the 11^th of February 2020 the International Committee on Taxonomy of Viruses called it the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Chhikara et al., 2020). The primary causative factor of infection transmission is the direct contact with patients such as: handshakes, contaminated surfaces and indirect inhalation of infected respiratory droplets, hence the incubation period which should be enforced around 14 days (Chhikara et al., 2020; Sohrabi et al., 2020).

The usual clinical signs are manifested as: dry cough, fever, headache, pneumonia, and breathing difficulties (dyspnea). Subsequently, the respiratory infection causes alveolar damage and respiratory failure, additionally, a decrease in the number of white blood cells, especially lymphocytes, were observed which, all in all, can lead to death in some cases (Zhou et al., 2020). The virus spread from China to other countries such as South Korea, Italy, Iran, USA, which, combined with the increasing incidence of infections worldwide made the World Health Organization (WHO) classify COVID-19 as a pandemic disease (Khalifa et al., 2020; Zingone et al., 2020). The recent update from the WHO on the 14^th of July 2020, confirmed a total around 12 million infected cases and more than 500,000 deaths reported in different regions and countries (World Health Organization, 2020a).

Since a long time, alternative herbal medicines have been used as a rich source for developing antiviral drugs (Lin et al., 2014). For instance, the Chinese herbal medicine was applied as the frontline remedies towards mild and moderate cases of COVID-19 infections. Based on the historical records of Chinese herbal medicine in preventing and treating several health ailments, Glycyrrhiza, bitter almond, gypsum, Trichosanthes, reed root, amomum, and ephedra were highly recommended to relieve cough, remove toxicity, increase immunity, and combat the fever of the admitted patients (Wan et al., 2020a). Similarly, many purified natural products have been administrated as anti-coronavirus. For instance, phenolic compounds isolated from Isatis indigotica and amentoflavone isolated from Torreya nucifera work as a 3CLprotease inhibitor and were used against SARS-CoV earlier. While saikosaponins B2 isolated from Bupleurum spp. was utilized against HCoV-229E and known to inhibit the viral attachment to host cells (Cheng et al., 2006; Islam et al., 2020). Furthermore, neem tree extract was used to help improve the immune system (Ray et al., 1996). The traditional medicinal herbs were described by the Chinese medical health care system in more than 23 provinces in China as alternatives for the prevention and treatment of the COVID-19 virus (Luo et al., 2020). The main aim of this review is to highlight the role of natural products especially, plants, microorganisms, marines, and/or their derivatives as a promising drug lead against different species of coronaviruses.

Coronaviruses

Coronaviruses types and classifications

Human coronaviruses (CoVs) are enveloped viruses, classified into various types namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV and SARS-CoV-2 (COVID-19) (Fig. 1 ) (Corman et al., 2018; Pillaiyar et al., 2020). The first two CoVs were reported in 1960′s, followed by the discovery of four other types in the 1970′s (Lau et al., 2006). The first four have been accompanied by symptoms such as the common cold, cough, fever, nasal congestion, sore throat, sneezing, and neurological diseases (Walsh et al., 2013; Woo et al., 2005). Their distribution was related mainly to temperate climates during the winter and spring months but geographically they have been observed all over the world (Talbot et al., 2009). HCoV-229E entered cells via binding to the aminopeptidase N receptor (CD13) found on the surface (Yeager et al., 1992). The incubation period ranged between 2 and 5 days (Lessler et al., 2009). The HCoV-229E virus replicated in the epithelial cell line of the trachea (Shirato et al., 2017). The First isolation for the HCoV-NL63 type was observed in a 7-month-old baby in early 2004 (Fielding, 2011). Different clinical evidences were reported and showed that HCoV-NL63 induced similar symptoms to those associated with HCoV-229E and HCoV-OC43 (Talbot et al., 2009). Since HCoV-NL63 and HCoV-229E can share 65% of their amino acid identity, they have an identical mechanism of cellular entry (van der Hoek et al., 2004).

Fig. 1.

Different types of coronavirus (CoVs) and their pathogenesis.

Severe Acute Respiratory Syndrome Coronavirus (SARS CoV) disproportionately infected adults, with notable severe symptoms i.e. fever, chills, myalgia, malaise, and headache, followed by a non-productive cough and dyspnea 3–5 days later (Fowler et al., 2003; Tsui et al., 2003). SARS-CoV was also named atypical pneumonia and was recorded as the first pandemic virus in human history (Peiris et al., 2003). Its incubation period is 2–10 days (World Health Organization, 2003). Young children and infants infected with SARS-CoV suffered from less severe symptoms than youth and adults (Bitnun et al., 2003). Infection with SARS-CoV type started by the inoculation of respiratory tract mucosa through Angiotensin-converting enzyme 2 (Li et al., 2003). Middle East Respiratory Syndrome Coronavirus (MERS-CoV) rarely infected children, but it can cause severe infections for youth. Infected cases with MERS-CoV suffered from many symptoms i.e. fever, cough, chills, sore throat, myalgia, arthralgia, dyspnea, pneumonia, diarrhea and vomiting (Assiri et al., 2013). It was isolated for the first time in a Saudi Arabian patient in 2012, then in another case from South Korea in 2015. About 2500 fatality cases were reported in February 2020 (Gao et al., 2016; Hilgenfeld and Peiris, 2013; Ye et al., 2020). Its incubation period ranged from 2 to 13 days (Coleman and Frieman, 2013). MERS-CoV infection started with inoculation of the respiratory tract mucosa mediated by functional receptors such as dipeptidyl peptidase 4 (DPP4) (Ng et al., 2016). Then the world faced a new challenge in December 2019, starting with the recording of the first SARS-CoV-2 case in Wuhan, Hubei province, China (Huang et al., 2020). The statistics reported on the of 14^th July 2020, confirmed that the number of fatality cases reached 570,288 total cases worldwide (World Health Organization, 2020a). SARS-CoV-2 causes severe respiratory infection accompanied by different symptoms i.e. fever, cough, dyspnea, myalgia, and headache (Huang et al., 2020). SARS-CoV-2 is mostly less pathogenic, but spreads more compared to SARS-CoV and MERS-CoV (Zhou et al., 2020).

SARS-CoV-2 origin, taxonomy and structure

In Wuhan, the capital of central China's Hubei province, the Coronavirus (COVID-19) outbreak appeared at the end of 2019, where China's Infectious Disease Information System recorded the first case on December 8, 2019 (Bai et al., 2020; Wu and McGoogan, 2020). The city's Huanan Seafood Market was the origin of the zoonotic virus SARS-CoV-2 which was transferred rapidly (Chan et al., 2020). The recent phylogenetic analysis detected that SARS-CoV-2 may be evolved from a strain found in bats, thus considered the natural reservoir host of SARS-CoV-2 (Chen et al., 2020a; Zhou et al., 2020). Till now, the researchers are not sure about the intermediate host (s) of SARS-CoV-2 or whether the infection can be transmitted directly from bat to human (Ye et al., 2020). It was then recognized as worldwide pandemic disease that can be transmitted rapidly between humans through droplets or direct contact (Li et al., 2020b).

2019-nCoV (COVID-19) also named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel member of the coronaviruses (Wang et al., 2020b). Nevertheless, it has a specific gene sequence that differentiates it from previously sequenced coronaviruses (Zhou et al., 2020). Interestingly, it has an 88% shared identity with SARS-CoV and about 50% to MERS-CoV, indicating that it belongs to the same species (Chen et al., 2020a; Lu et al., 2020). The phylogenetic analysis done to classify SARS-CoV-2 revealed that it falls into the Sarbecovirus subgenus of the genus Betacoronavirus (Lu et al., 2020; Zhu et al., 2020).

In general, HCoVs are long and positive single stranded RNA viruses characteristic of two groups of proteins; the first group is namely the structural proteins: Spike (S), Nucleocapsid (N), Matrix (M), and Envelope (E) (Fig. 2 ), while the second group is non-structural proteins: proteases (nsp3 and nsp5) and RdRp (nsp12) (Elfiky et al., 2017). In the case of SARS-CoV-2, the densely glycosylated spike protein found on the outer surface is arranged in this way in order to facilitate the recognition, attachment, and entry into the host cell (Ibrahim et al., 2020). Similarly, the genetic material of SARS-CoV-2 is a positive sense RNA strand (Chhikara et al., 2020). SARS-CoV-2 was described with a transmission electron microscope (TEM) where the double-wall surface of SARS-CoV-2 was seen, but it gives only a poor description of the different organelles in the cytoplasm (Chhikara et al., 2020; Walls et al., 2020). Thus, it was assumed that SARS-CoV-2 has distinct ultrastructural features similar to the coronavirus family such double-membrane vesicles, large granular areas of cytoplasm and nucleocapsid inclusions, in addition to viral proteins and genetic material RNA (Chhikara et al., 2020).

Fig. 2.

Illustrating the structure of SARS-CoV-2 (COVID-19).

Replication, pathogenesis and transmission

SARS-CoV and SARS-CoV-2 (COVID-19) are similar in the mechanism of replication (He et al., 2020). Their replication begin with the binding of its spike protein (S) into the host's cell surface molecules (Sahin et al., 2020). Usually, (S) protein is divided functionally into the S1 domain, responsible for binding to human receptors, and the S2 domain is responsible for cell membrane fusion (He et al., 2004). SARS-CoV-2 enters the host cells through recognition of human receptor angiotensin-converting enzyme 2 (ACE2) (Zhou et al., 2020). RNA material of SARS-CoV-2 undergoes replication and transcription after the fusion with the plasma membrane. Replicase proteins of SARS-CoV-2 are generated from translation of positive sense RNA genomes through open reading frame 1a/b (ORF1a/b). These proteins use positive sense RNA as a template to generate full-length negative sense RNA. Then proteins are collected with new RNA genome assembly in the endoplasmic reticulum (ER) and Golgi-apparatus (Fig. 3 ) (He et al., 2020). Biophysical and structural analysis confirmed that the S protein of SARS-CoV-2 has an affinity to bind with ACE2 about 10–20 times higher than the S protein of SARS-CoV (Wrapp et al., 2020). The high affinity of the S protein for human ACE2 can facilitate the spread of SARS-CoV-2 between humans (Zhou et al., 2020).

Fig. 3.

Mechanism of SARS-CoV-2 replication.

The studies conducted on the COVID-19 infection mechanism showed an increase in leukocyte levels, plasma pro-inflammatory cytokines i.e. IL-6, and blood C-reactive protein values from the normal range (Lei et al., 2020). Lower numbers of T and B lymphocytes in peripheral blood are observed and coagulation parameters i.e. d-Dimer raise abnormally (Lin et al., 2020). The main pathogenesis of the COVID-19 infection is described as extreme pneumonia, RNA aemia, and acute cardiac injury (Huang et al., 2020). The high rate of renal failure was observed in patients with COVID-19, suggesting the development of renal dysfunction (Li et al., 2020a; Li et al., 2020b).

The human-to-human spread is now the primary way of transmission of the infection; from both symptomatic and asymptomatic individuals. The transmission from symptomatic patients occurs to nearby individuals but does not occur through air. Transmission from asymptomatic individuals occurs through direct contact, handshaking (Kam et al., 2020), touching contaminated surfaces (Bai et al., 2020) or droplets spread by coughing or sneezing then touching the mouth, nose or eyes (Pan et al., 2020b). Therefore, the human-to-human transmission depends on proximity and increased population density. Also, Leung et al. (2020) proved that inadequate use of masks could lead to increased chances of infection transmission (Leung et al., 2020). A study conducted by Chen et al. (2020a) on confirmed pregnant women cases, demonstrated no evidence of trans-placental transmission. These women underwent cesarean sections, so the transmission by vaginal birth is still under debate (Chen et al., 2020a).

In the previous years, SARS-CoV (2003) infected about 8098 individuals in 26 regions around the world with a mortality rate of 9% (World Health Organization, 2003). On the other hand, SARS-CoV-2 has infected roughly 7,690,708 individuals in more than 200 countries until the 14^th of June 2020 (World Health Organization, 2020b). Meaning that the transmission of SARS-CoV-2 is higher than SARS-CoV. Li et al., 2020a proved that the high spread of COVID-19 is due to the genetic recombinant S protein (Li et al., 2020a). Initial reports identified two species of snakes that may be a reservoir of SARS-CoV-2 (Ji et al., 2020; Rothan and Byrareddy, 2020). Mammals or birds are the only evidenced reservoirs of SARS-CoV-2 (Bassetti et al., 2020). Genomic sequence analysis of SARS-CoV-2 showed an 88% identity share with two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses (Chan et al., 2020; Lu et al., 2020; Wan et al., 2020b). Despite the fact that the genetic material of SARS-CoV-2 is compatible with other types of coronavirus, its gene sequences remarkably differ from previous sequences of other CoV types (Zhou et al., 2020). The genetic studies of SARS-CoV-2 showed that its sequence shared 79% identity with the other CoVs types (Lu et al., 2020).

Rational use of natural products based antiviral agents

Drugs management in preclinical studies (in vivo, in vitro)

Despite huge efforts, the world has been unable to discover potential therapies or vaccines against COVID-19, thus most of the scientific efforts are now allocated towards trying to locate a proper medication from the old conventional drugs applied earlier for previous coronavirus varieties, among them are HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 which caused mild upper respiratory disease in humans, as well as severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV (Pillaiyar et al., 2020). Natural products, mainly plants, remain as a rich source of novel therapeutic agents for the treatment of different human illnesses (Yang et al., 2020b) . In this context, many natural product derivative therapeutic agents have been reported to inhibit entry and replication of many coronaviruses; SARS, MERS, etc. (in vitro and in vivo) (Tables 1 and 2 ; Fig. 4 –6 )

Fig. 5.

Structures of isolated anti-viral compounds of marine origin or their derivatives.

Table 1.

List of isolated anti-viral natural products compounds and their derivatives.

Compound name, chemical class	Origin	Mechanism of action	Virus type	IC50 or EC50 (CC50) value µg/ml	Reference
Plants
2,3,4,6,7-pentamethoxy-12,13-dihydro-11H dibenzo[f,h]pyrrolo- [1,2-β] isoquinolin-10-ium (ND), alkaloid (1)	Ficus septica L.	Inhibits viral replication	TGEV	14.906±2468 (>100,000) nM	Yang et al., 2010a
3,14α-dihydroxy-4,6,7-trimethoxyphenanthroindolizidine (ND), alkaloid (2)	T. ovata L.	Inhibits viral replication	TGEV	8 ± 2 (59.943±2786) nM	Yang et al., 2010a
3,14α -dihydroxy-6,7-dimethoxyp-henanthroindolizidine (ND), alkaloid (3)	T. ovata L.	Inhibits viral replication	TGEV	18±1 (31,632±1192) nM	Yang et al., 2010a
3′-O-methyldiplacol (N), flavonoid (4)	Paulownia tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	9.5 ± 0.10 µM	Cho et al., 2013
3′-O-methyldiplacone (N), flavonoid (5)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	13.2 ± 0.14 µM	Cho et al., 2013
3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane (N), flavonoid (6)	Broussonetia papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	48.8 ± 6.6 µM	Park et al., 2017
			SARS-CoV	30.2 ± 6.8 µM
3β,12-diacetoxyabieta-6,8,11,13-tetraene (N), diterpenoid (7)	Juniperus formosana L.	Inhibits viral replication	SARS-CoV	1.57 (303.3) µM	Wen et al., 2007
4`-Hydroxychalcone (ND), flavonoid (8)	Cinnamomum spp.	Inhibits viral replication	HCoV-OC43	1.52 (>20) µM	Jarvill-Taylor et al., 2001; Orlikova et al., 2011; Shen et al., 2019
			HCoV-NL63	7.25 (>20) µM
			MERS-CoV	10.23 (>20) µM
			MHV-A59	9.75 (>20) µM
4`-O-methyldiplacol (N), flavonoid (9)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	9.2 ± 0.13 µM	Cho et al., 2013
4`-O-methyldiplacone (N), flavonoid (10)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	12.7 ± 0.19 µM	Cho et al., 2013
4-hydroxyisolonchocarpin (N), flavonoid (11)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	171.6 ± 10.2 µM	Park et al., 2017
			SARS-CoV	202.7 ± 3.9 µM
6,7-dehydroroyleanone (N), diterpenoid (12)	Chamaecyparis obtusa var. formosana	Inhibits viral replication	SARS-CoV	5.55 (89.7) µM	Wen et al., 2007
6-geranyl-4′,5,7-trihydroxy-3′,5′- dimethoxyflavanone (N), flavonoid (13)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	13.9 ± 0.18 µM	Cho et al., 2013
7β -hydroxydeoxycryptojaponol (N), diterpenoid (14)	C. japonica L.	Inhibits viral replication	SARS-CoV	1.15 (127) µM	Wen et al., 2007
8β-hydroxyabieta-9(11),13‑dien-12-one (N), diterpenoid (15)	C. obtuse var. formosana	Inhibits viral replication	SARS-CoV	1.47 (> 750) µM	Wen et al., 2007
Acetyl-O-methyltylophorinidine (ND), alkaloid (16)	T.indica L.	Inhibits viral replication	TGEV	403 ± 22 (> 100,000) nM	Govindachari et al., 1973; Yang et al., 2010a
Aloeemodin (N), anthraquinone (17)	Isatis indigotica	Inhibits enzymatic activity of virus	SARS-CoV	366 (11,592) µM	Lin et al., 2005
Baicalin (N), flavonoid (18)	Scutellaria baicalensis	Inhibits the enzymatic activity	SARS-CoV	12.5–25 (> 100) µg/ml	Chen et al., 2004; Deng et al., 2012
Berbamine (N),  bis-benzylisoquinoline alkaloids  (19)	Berberis amurensis	Inhibits viral replication	HCoV-OC43	1.48 (> 20) µM	Meng et al., 2013; Shen et al., 2019
			HCoV-NL63	9.46 (> 20) µM
			MERS-CoV	13.14 (> 20) µM
			MHV-A59	10.91 (> 20) µM
Beta-sitosterol (N), steroid (20)	I. indigotica	Inhibits enzymatic activity of virus	SARS-CoV	1210 (1475) µM	Lin et al., 2005
Betulonic acid (N), triterpene (21)	J. formosana L.	Inhibits viral replication	SARS-CoV	0.63 (112) µM	Wen et al., 2007
Broussochalcone A (N), polyphenol (22)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	42.1 ± 5.0 µM	Park et al., 2017
			SARS-CoV	88.1 ± 13.0 µM
Broussochalcone B (N), polyphenol (23)	Broussonetia papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	112.9 ± 10.1 µM	Park et al., 2017
			SARS-CoV	57.8 ± 0.5 µM
Broussoflavan A (N), flavonoid (24)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	49.1 ± 7.5 µM	Park et al., 2017
			SARS-CoV	92.4 ± 2.1 µM
Cedrane-3 β,12-diol (N), sesquiterpenoid (25)	J. formosana L.	Inhibits viral replication	SARS-CoV	> 10 (> 750) µM	Wen et al., 2007
Cepharanthine, (N), (bis-benzylisoquinoline alkaloids) (26)	S. tetrandra	Inhibits viral S and N protein expression/ Suppressed the replication	HCoV-229E	729.7 nM	Kim et al., 2019
Chloroquine (S*), alkaloid (27)	Cinchona spp.	Inhibits viral replication	HCoV-OC43	0.33 (> 20) µM	Keyaerts et al., 2009; Oliveira et al., 2009; Shen et al., 2019
			HCoV-NL63	4.89 (> 20) µM
			MERS-CoV	16.44 (> 20) µM
			MHV-A59	15.92 (> 20) µM
			SARS-CoV	8.8 ± 1.2 µM
Conessine (N), steroid alkaloid (28)	Holarrhena antidysenterica	Inhibits viral replication	HCoV-OC43	2.34 (> 20) µM	Dua et al., 2013; Shen et al., 2019
			HCoV-NL63	10.75 (> 20) µM
			MERS-CoV	4.98 (> 20) µM
			MHV-A59	11.46 (> 20) µM
Cryptojaponol (N), diterpenoid (29)	Cryptomeria japonica L.	Inhibits viral replication	SARS-CoV	> 10 (78.5) µM	Wen et al., 2007
Dehydroabieta-7-one, (N), diterpenoid (30)	C. obtuse var formosana	Inhibits viral replication	SARS-CoV	4 (305.1) µM	Wen et al., 2007
Emetine dihydrochloride hydrate (S*), alkaloid (31)	Carapichea ipecacuanha L.	Inhibits RNA, DNA, and protein synthesis	HCoV-OC43	0.30 (2.69) µM	Dyall et al., 2017; Pillaiyar et al., 2020; Shen et al., 2019
			HCoV-NL63	1.43 (3.63) µM
			MERS-CoV	0.34 (3.08)/ 0.014 µM
			MHV-A59	0.12 (3.51) µM
			SARS-CoV	0.05 µM
Fangchinoline, (N), (Bis-benzylisoquinoline alkaloids) (32)	S. tetrandra	Inhibits viral S and N protein expression	HCoV-229E	919.2 nM	Kim et al., 2019
Ferruginol, (N), diterpenoid (33)	C. obtuse var. formosana	Inhibits viral replication	SARS-CoV	1.39 (80.4) µM	Wen et al., 2007
Glycyrrhizin (N), terpenoid saponin (34)	Glycyrrhiza glabra L.	Inhibits replication, adsorption and penetration of the virus at early steps of the replicative cycle	SARS-CV	300 mg/l	Cinatl et al., 2003
Harmine (N), alkaloid (35)	Peganum harmala	Inhibits viral replication	HCoV-OC43	1.90 (> 20) µM	Moloudizargari et al., 2013; Shen et al., 2019
			HCoV-NL63	13.46 (> 20) µM
			MERS-CoV	4.93 (> 20) µM
			MHV-A59	13.77 (> 20) µM
Hesperetin, (N), flavonoid (36)	Citrus aurantium	Inhibits viral replication	SARS-CoV	8.3 (2718 µM)	Lin et al., 2005
Hinokinin (N), lignoid (37)	C. obtuse var.	Inhibits viral replication	SARS-CoV	> 10 (> 750) µM	Wen et al., 2007
Indigo (N), alkaloid (38)	I. indigotica	Inhibits enzymatic activity of virus	SARS-CoV	752 (7375) µM	Lin et al., 2005
Indirubin (N), alkaloid (39)	I. indigotica	Inhibits enzymatic activity of virus	SARS-CoV	–	Lin et al., 2005
Kazinol A (N), flavonoid (40)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	88.5 ± 3.9 µM	Park et al., 2017
			SARS-CoV	84.8 ± 10.4 µM
Kazinol B (N), flavonoid (41)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	94.9 ± 13.1µM	Park et al., 2017
			SARS-CoV	233.3 ± 6.7 µM
Kazinol F (N), flavonoid (42)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	39.5 ± 5.1 µM	Park et al., 2017
			SARS-CoV	43.3 ± 10.4 µM
Kazinol J (N), flavonoid (43)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	55.0 ± 1.3 µM	Park et al., 2017
			SARS-CoV	64.2 ± 1.7 µM
Luteolin (N), flavonoid (44)	Rhodiola kirilowii L.	Inhibits entry of virus to cell	SARS-CoV	10.6 µM (0.155) mM	Yi et al., 2004
Lycorine (N), alkaloid (45)	Lycoris radiata (L'Hér.)	Inhibits cell division, antineoplastic, antiviral	HCoV-OC43	0.15 (4.37) µM	Li et al., 2005; Pillaiyar et al., 2020; Shen et al., 2019
			HCoV-NL63	0.47 (3.81) µM
			MERS-CoV	1.63 (3.14) µM
			MHV-A59	0.31 (3.51) µM
			SARS-CoV	0.0157 (14.98) µM
Mimulone (N), flavonoid (46)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	14.4 ± 0.27 µM	Cho et al., 2013
N-acetylglucosamine (N), alkaloid (47)	Urtica dioica agglutinin	Inhibits viral replication	SARS-CoV	2.6 ± 3.7 (12.5 ± 4.4 ) (µg/ml	Kumaki et al., 2011; Liu et al., 2008
Papaverine (N), alkaloid (48)	Papaver somniferum L.	Inhibits viral replication	HCoV—OC43	1.61 (12.11) µM	Labanca et al., 2018; Shen et al., 2019
			HCoV-NL63	7.32 (11.71) µM
			MERS-CoV	9.45 (11.98) µM
			MHV-A59	11.46 (12.44) µM
Papyriflavonol A (N), flavonoid (49)	B. papyrifera	Inhibits coronavirus proteases enzyme	MERS-CoV	112.5 ± 7.3 µM	Park et al., 2017
			SARS-CoV	103.6 ± 17.4µM
Pinusolidic acid, (N), diterpenoid (50)	C. obtuse var.	Inhibits viral replication	SARS-CoV	4.71 (> 750) µM	Wen et al., 2007
Pristimerin (N), triterpenoid (51)	Pristimerae indica, Tripterygium regelii	Inhibits viral replication	HCoV-OC43	1.99 (> 20) µM	Li et al., 2019; Ryu et al., 2010; Shen et al., 2019
			HCoV-NL63	1.63 (> 20) µM
			MERS-CoV	13.87 (> 20) µM
			MHV-A59	9.17 (> 20) µM
			SARS-CoV	5.5 µM
Saikosaponin A (N), triterpenoid saponins (52)	Bupleurum spp., Heteromorpha spp., Scrophularia scorodonia	Inhibits viral attachment and penetration into cells	HCoV-229E	8.6 ± 0.3 (228.1 ± 3.8) µmol/l	Cheng et al., 2006
Saikosaponin B2 (N), triterpenoid saponins (53)	Bupleurum spp., Heteromorpha spp., S. scorodonia	Inhibits viral attachment and penetration into cells	HCoV-229E	1.7 ± 0.1 (383.3 ± 0.2) µmol/l	Cheng et al., 2006
Saikosaponin C (N), triterpenoid saponins (54)	Bupleurum spp., Heteromorpha spp., S. scorodonia	Inhibits viral attachment and penetration into cells	HCoV-229E	19.9 ± 0.1 (121.5 ± 0.1) µmol/l	Cheng et al., 2006
Saikosaponin D (N), triterpenoid saponins (55)	Bupleurum spp., Heteromorpha spp., S. scorodonia	Inhibits viral attachment and penetration into cells	HCoV-229E	13.2 ± 0.3 (176.2 ± 0.2) µmol/l	Cheng et al., 2006
Savinin (N), lignoid (56)	C. obtuse var.	Inhibits viral replication Inhibits enzymatic activity of virus	SARS-CoV	25, 1.13, (> 750) µM	Wen et al., 2007
Sinigrin (N), glycoside (57)	I. indigotica	Inhibits enzymatic activity of virus	SARS-CoV	217 (> 10,000) µM	Lin et al., 2005
Tetrandrine, (N), (bis-benzylisoquinoline alkaloids) (58)	Stephania tetrandra	Inhibits viral S and N protein expression	HCoV-229E	295.6 nM	Kim et al., 2019
Tetra-O-galloyl-d-glucose (N), tannin (59)	Galla chinensis L.	Inhibits entry of virus to cell	SARS-CoV	4.5 µM (1.08 mM)	Yi et al., 2004
Tomentin A (N), coumarin (60)	Paulownia tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	6.2 ± 0.04 µM	Cho et al., 2013
Tomentin B (N), coumarin (61)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	6.1 ± 0.02 µM	Cho et al., 2013
Tomentin C (N), coumarin (62)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	11.6 ± 0.13 µM	Cho et al., 2013
Tomentin D (N), coumarin (63)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	12.5 ± 0.22 µM	Cho et al., 2013
Tomentin E (N), coumarin (64)	P. tomentosa (Thunb).	Inhibits PLpro enzyme	SARS-CoV	5.0 ± 0.06 µM	Cho et al., 2013
Tylophorine (N), alkaloid (65)	T. indica L.	Inhibits viral replication	TGEV	95±17 (> 100.000) nM	Yang et al., 2010a
Tylophorinine (N), alkaloid (66)	T. indica L.	Inhibits viral replication	TGEV	82 ± 8 (> 100.000) nM	Yang et al., 2010a
α-cadinol, (N), sesquiterpenoid (67)	C. obtuse var.	Inhibits viral replication	SARS-CoV	4.44 (76.8) µM	Wen et al., 2007
Marine
Esculetin-4-carboxylic acid ethyl ester (N), coumarin (68)	Axinella cf. corrugate, Sponge	Inhibit enzymatic activity of virus	SARS-CoV	> 800 µmol l-1, 112 µmol l-1	Lira et al., 2007
Halitunal (N), diterpene aldehyde (69)	Hulimeda tuna, Algae	Reduction in cell fusion and cytopathic effects	Murine coronavirus	20 µg	Koehn et al., 1991
Mycalamide A (N), alkaloid (70)	Mycale sp., Sponge	Protein synthesis inhibitors of virus	MHV-A59	Tested dose 0.2 µg/kg daily	Donia and Hamann, 2003
Microorganisms
Antimycin A (N), alkaloid (71)	Streptomyces spp., Bacteria	Antibiotic	HCoV-OC43	1.65 (3.62) µM	Shen et al., 2019; Van Tamelen et al., 1961
			HCoV-NL63	6.05 (4.21) µM
			MERS-CoV	6.89 (4.32) µM
			MHV-A59	5.42 (3.98) µM
Cycloheximide (N), alkaloid (72)	Streptomyces spp., Bacteria	Protein synthesis inhibitor	HCoV-OC43	0.43 (3.12) µM	Shen et al., 2019; Sisler and Siegel, 1967
			HCoV-NL63	2.64 (3.24) µM
			MERS-CoV	2.56 (2.96) µM
			MHV-A59	5.21 (3.19) µM
Monensin sodium (ND), salt (73)	Streptomyces cinnamonensis, Bacteria	Inhibit viral replication	HCoV-OC43	3.81 (>20) µM	Łowicki and Huczyński, 2013; Pillaiyar et al., 2020; Shen et al., 2019
			HCoV-NL63	1.54 (>20) µM
			MERS-CoV	3.27(>20) µM
			MHV-A59	0.18 (>20) µM
Mycophenolate mofetil (ND) (74)	Penicillium spp., Fungus	Immune suppressant, antineoplastic, antiviral	HCoV-OC43	1.58 (3.43) µM	Bittencourt et al., 2000; Pillaiyar et al., 2020; Shen et al., 2019; Sollinger, 2004
			HCoV-NL63	0.23 (3.01) µM
			MERS-CoV	1.54 (3.17) µM
			MHV-A59	0.27 (3.33) µM
Mycophenolic acid (N) (75)	Penicillium spp., Fungus	Immune suppressant, antineoplastic, antiviral	HCoV-OC43	1.95 (3.55) µM	Cinatl et al., 2003; Hart et al., 2014; Pillaiyar et al., 2020; Shen et al., 2019; Sollinger, 2004
			HCoV-NL63	0.18 (3.44) µM
			MERS-CoV	1.95 (3.21) µM
			MHV-A59	0.17 (4.18) µM
			SARS-CoV	> 0.15
Valinomycin (N), Peptide (76)	Streptomyces sp., Bacteria	Antibiotic	HCoV-OC43	4.43 (6.15) µM	Cheng, 2006; Shen et al., 2019
			HCoV-NL63	1.89 (4.12) µM
			MERS-CoV	6.07 (5.88) µM
			MHV-A59	6.78 (5.11) µM
Oligomycin (N), Macrolide (77)	Streptomyces sp., Bacteria	Inhibits viral replication	HCoV-OC43	0.19 (6.56) µM	Shen et al., 2019; Yang et al., 2010b
			HCoV-NL63	2.63 (4.26) µM
			MERS-CoV	0.21 (5.16) µM
			MHV-A59	6.43 (6.78) µM

TGEV: Coronavirus infected Pigs.

Table 2.

List of plants extracts used as anti-coronaviruses.

Plants	Type of extract	Organism/ Mechanism	IC50 or EC50 (CC50) value ug/ml	References
Artemisia annua L., Whole plant	EtOH	SARS-CoV Reduces RNA replication	34.5 (1053)	Li et al., 2005
Cassia tora (CTH)	EtOH	SARS-CoV Inhibits viral replication Inhibits enzymatic activity	8.43 (> 500) > 50	Wen et al., 2011
Celastrus orbiculatus Thunb.	EtOH	SARS-CoV NR	19.4	Kumar et al., 2013
	EtOAc	SARS-CoV NR	17.8
	Aqueous	SARS-CoV NR	38.7
Cibotium barometz (CBE)	EtOH	SARS-CoV Inhibits viral replication, Inhibits enzymatic activity	8.42 (> 500) > 50	Wen et al., 2011
C. barometz (CBM)	EtOH	SARS-CoV Inhibits viral replication Inhibits enzymatic activity	> 10 (> 500) 39	Wen et al., 2011
Dioscorea batatas (DBM)	EtOH	SARS-CoV Inhibits viral replication Inhibits enzymatic activity	8.06 (> 500) 44	Wen et al., 2011
Echinacea purpurea, Roots	Aqueous ethanol	SARS-CoV Inhibits viral replication	50	Signer et al., 2020
		MERS-CoV Inhibits viral replication	50
		HCoV-229E Inhibits viral replication	3.2
Gentiana scabra (GSH), Rhizomes	EtOH	SARS-CoV Inhibits viral replication Inhibits enzymatic activity	8.70 (> 500) > 50	Wen et al., 2011
J. oxycredrus, Berries	Essential oil	SARS-CoV Inhibits viral replication	270	Loizzo et al., 2008
l. nobilis, Berries	Essential oil	SARS-CoV Inhibits viral replication	120	Loizzo et al., 2008
Lindera aggregate Sims, Roots	EtOH	SARS-CoV Reduces RNA replication	88.2 (1374)	Li et al., 2005
Lycoris radiata (L'Hér.), Stem	EtOH	SARS-CoV Reduces RNA replication	2.4 (886.6)	Li et al., 2005
P. palaestina, Fruits	Essential oil	SARS-CoV Inhibits viral replication	> 1000	Loizzo et al., 2008
Pyrrosia lingua Mirb., Leaves	CHCl₃	SARS-CoV Reduce RNA replication	43.2 (2378)	Li et al., 2005
T. orientalis, Fruits	Essential oil	SARS-CoV Inhibits viral replication	130	Loizzo et al., 2008
Taxillus chinensis (TCH)	EtOH	SARS-CoV Inhibits viral replication Inhibits enzymatic activity	5.39 (> 500) > 50	Wen et al., 2011
Toona sinensis Roem Leaves	Aqueous	SARS-CoV Inhibits viral replication	30 (> 500)	Chen et al., 2008

Fig. 4.

Structures of isolated anti-viral compounds of plant origin and their derivatives.

Fig. 6.

Structures of isolated anti-viral compounds of microbial origin or their derivatives.

Glycyrrhizin (34) is an active terpenoid saponin compound isolated from liquorice roots (Glycyrrhiza glabra L.). Liquorice roots have been used in traditional medicine as prophylactic agent for gastric and duodenal ulcers, anti-inflammatory, contraceptive, laxative, anti-asthmatic, galactagogue, and antiviral, and expectorant (Damle, 2014; Sato et al., 1996). Cinatl et al. demonstrated that glycyrrhizin inhibited SARS virus replication by inhibition of adsorption. The penetration of the virus at early steps of the replicative cycle was stopped at both concentrations of (EC₅₀ of 300 mg/l) and CC₅₀ value of >20 000 mg/l in comparison to ribavirin (positive control) when greater than >1000 that could not be tolerated by the target tissue or organs (Cinatl et al., 2003).

In 2005, Li and his co-authors tested around 200 Chinese medicinal plants against Severe Acute Respiratory Syndrome associated coronavirus (SARS-CoV) using MTS assay. The results demonstrated that 4 of the 200 plants extracts, namely L. radiata (L'Hér.), A. annual ., P. lingua Mirb. and L. aggregate Sims, showed superior activity at EC₅₀ of 2.4, 34.5, 43.2 and 88.2 µg/ml respectively compared with interferon alpha as a positive control (EC₅₀ = 660.3 IU/ml). Four potent extracts recorded CC₅₀ values ranged between 886.6 ± 35.0 to 2378.0 ± 87.3 µg/ml. CC₅₀ was determined based on reducing cell viability by using different concentration of extracts. As L. radiata (L'Hér.) was the most active one, it was subjected to fractionation and purification to find the most active compound, identified as lycorine (45). Lycorine is an alkaloid compound that gave EC₅₀ of 15.7 nM and CC₅₀ value of 14,980.0 nM against SARS-CoV (Li et al., 2005). Lycorine have been investigated later against the other types of coronaviruses, HCoV-OC43, HCoV-NL63, MERS-CoV and MHV-A59 to give EC₅₀ values ranging from 0.15 µM to 1.63 µM (Shen et al., 2019).

Emetine is a natural plant alkaloid of ipecac (Carapichea ipecacuanha L.), emetine dihydrochloride (31), a derivative of emetine inhibiting the viral protein synthesis of coronaviruses, with an EC₅₀ value of 0.12 to 1.43 µM. Emetine hydrochloride revealed the strongest anti-CoV activities against MERS-CoV and SARS-CoV with the lowest EC₅₀ of 0.014 and 0.05 µM, whilst the activity against HCoV-NL63, HCoV-OC43, MERS-CoV and MHV-A59 showed EC₅₀ values of 1.43 µM, 0.30, 0.34 and 0.12 µM respectively via blocking of viral propagation at an early stage of infection, thereby minimizing the chance of the virus to adapt and acquire drug resistance. It also has CC₅₀ values of 3.63, 2.69, 3.08 and 3.51 µM respectively (Dyall et al., 2017; Shen et al., 2019).

Toona sinensis Roem, is a Chinese traditional plant belonging to the Meliaceae family. In the folk medicine, the leaves of the plant were used to treat gastric ulcers, enteritis, dysentery, cerebrovascular, and cardiovascular diseases (Kakumu et al., 2014). TSL-1, a fraction of the aqueous extract of the plant leaves showed anti-viral activity against SARS-coronavirus with EC₅₀ of 30 µg/ml and CC₅₀ value > 500 µg/ml via inhibition of the viral replication. Determination of CC₅₀ takes place by decreasing the cell viability by 50% (Chen et al., 2008). Another study was conducted by Wen et al., where 200 plants were tested and only five of them, namely Gentiana scabra, Dioscorea batatas, Cassia tora, and Taxillus chinensis, exerted survival inhibition of SARS-CoV (Wen et al., 2011). The plants possess a wide range of folk applications including liver disorder, inflammation and pneumonia treatment (Liang et al., 2007; Oh et al., 2004; Pawar and D'mello, 2011; Zhang et al., 2013). The potent inhibition of SARS-CoV viral enzymatic activity (SARS-CoV 3CLprotease) occurred between 25 and 200 µg/ml and the most potent plants were C. barometz and D. batatas with IC₅₀ value of 39 and 44 µg/ml respectively. The six plant extracts recorded the same CC₅₀ value of > 500 µg/ml in comparison with valinomycin (positive control) that has value of 75.01 µg/ml. The determination of CC₅₀ showed that reduction of cell viability by 50% and there was no effect on the growth of host cells, indicating the effectiveness and safety of these extracts (Wen et al., 2011).

Celastrus orbiculatus Thunb. family (Celastraceae), a Chinese herbal plant, traditionally used in the treatment of fever, chills, edema and bacterial infection (Wu et al., 2004), showed significant effect via inhibition of the 3CL^pro enzyme. Three different extracts (EtOH, EtOAc and water fraction) have been tested against SARS-CoV infection, and exhibited IC₅₀ values of 19.4, 17.8 and 38.7 μg/ml respectively (Kumar et al., 2013). Similarly, hydroethanolic extraction of Echinacea purpurea plant roots showed potent activity against HCoV-229E, SARS-CoV and MERS-CoV with IC₅₀ values of 3.2, 50 and 50 µg/ml respectively (Signer et al., 2020).

Furthermore, the essential oils of many plants play an important role against viral diseases i.e. Laurus nobilis, Juniperus oxycedrus ssp. oxycedrus, Thuja orientalis, Cupressus sempervirens ssp. pyramidalis, Pistacia palaestina, Salvia officinalis, and Satureja thymbra. The essential oils were investigated against SARS-CoV and HSV-1 viruses. The potent activity of L. nobilis oil was reported against SARS-CoV with IC₅₀ value of 120 µg/ml. The plant oil is characterized by the excitation of β-ocimene, 1,8-cineole, α-pinene, and β-pinene as the principle constituents. These plants act via the inhibition of viral replication (Loizzo et al., 2008).

Marines natural products, i.e. halitunal (69), mycalamide (70) and esculetin-4-carboxylic acid ethyl ester (68) showed antiviral activity against coronaviruses. Halitunal is a diterpene aldehyde isolated from the marine alga Halimeda tuna, known to exert an impact against murine coronavirus strain A59 at a dose of 20 µg by reduction of cell fusion (Koehn et al., 1991). Mycalamide is an alkaloid compound isolated from the Mycale sp. sponge that inhibited the MHV-A59 coronavirus replication by blocking the protein synthesis (Donia and Hamann, 2003). Additionally, esculetin-4-carboxylic acid ethyl ester, is a coumarin compound derived from the Axinella cf. corrugate sponge that down-regulates the SARS 3CL-protease (Lira et al., 2007).

Streptomyces spp. compounds including monensin sodium (73), cycloheximide (72), oligomycins (77), valinomycin (76), and antimycin A (71) were isolated and investigated in opposition to SARS-CoV-2. Monensin sodium is an antibacterial salt isolated from Streptomyces cinnamonensi actinobacteria culture containing glucose, soybean oil, and grit (Łowicki and Huczyński, 2013). Monensin sodium exhibited antiviral activity against diverse coronaviruses (EC₅₀ = 0.18–3.81 µM) (Shen et al., 2019). Formerly, monensin and monensin sodium inhibited avian infectious bronchitis virus replication by blocking glycoprotein transport to plasma membranes at the level of the Golgi complex (Alonso-Caplen et al., 1984; Niemann et al., 1982) . Cycloheximide, oligomycins, valinomycin and antimycin A were used against a wide spectrum of Coronaviruses by inhibiting protein synthesis and viral replication with EC₅₀ of (0.43–5.21), (0.19 -6.43), (1.89–6.78) and (1.65–6.89), respectively. As well these compounds recorded CC₅₀ value range between (2.96- 3.24), (4.26–6.78), (4.12–6.15) and (3.62–4.32) respectively (Shen et al., 2019).

Mycophenolic acid (MPA) (75) was first isolated from Penicillium spp. fungi by Bartolomeo Gosio in 1893 and was reported to have an immunosuppressive activity against psoriasis (Sollinger, 2004). Recently, mycophenolic acid was investigated against different types of coronavirus using a high-throughput screening approach, where the MPA showed potent anti- MHV-A59 activity in vitro at an EC₅₀ value of 0.17 µM compared to of HCoV-OC43, HCoV-NL63 and MERS-CoV (EC₅₀ values ranging from 0.18 to 1.95 µM). The value of CC₅₀ of MHV-A59 equals 4.18 µM that is greater than the values of HCoV-OC43, HCoV-NL63 and MERS-CoV ranging from 3.21 to 3.55 µM (Shen et al., 2019). Another promising MPA derivative called mycophenolate mofetil (74) was reported to be an immunosuppressant, antineoplastic, and antiviral agent against HCoV-OC43, HCoV-NL63, MERS-CoV and SARS-CoV at EC₅₀ of 1.58, 0.23, 1.54 and 0.27 µM. The CC₅₀ of this compound ranged from 3.01 to 3.43 µM. The two compounds have similar chemical structures, but MPA showed a higher activity against MHV-A59 (EC₅₀ = 0.17 µM) (Shen et al., 2019).

Curative efficacy of clinical studies and approved drugs

For a long time, natural products and their molecular frameworks constitute valuable starting points or sources for drug discovery (El-Seedi et al., 2019; Rodrigues et al., 2016). In line with Newman and Cragg, the number of antiviral drugs approved by the FDA in the period between 1981 to 2019 are 186 drugs, among them 87 are vaccines like FluMist®, Invivac®, Bilive®, Anflu®, Afluria® and Optaflu®, and are used against the influenza virus, 26 are synthetic but the pharmacophores are natural products, 17 are biological sources like peptides and proteins and 6 are natural products derivatives such as Tamiflu®, Zanamivir® and Virreal®, 21 are synthetic drugs (NP pharmacophore)/ mimics of natural products and other 19 compounds are synthetics (Newman and Cragg, 2020).

Nowadays, there are around 80 running and pending clinical trials in China in a serious attempt to find a potential treatment for COVID-19 (Maxmen, 2020). In 2020, several compounds isolated from natural products (Fig. 7 ; Table 3 ) were tested against coronavirus (COVID-19), i.e. Xiyanping (Mix of 78 and 79). Xiyanping, is a semi-synthetic product derived from the active components of the Andrographis paniculata plant, and licensed in China as an anti-inflammatory agent (Chong et al., 2013; Xiao et al., 2013). Xiyanping injection was investigated on 426 patients diagnosed with moderate to severe SARS-CoV-2 infection, every patient was injected with 10–20 ml of Xiyanping at 500 mg per 20 ml daily plus lopinavir/ritonavir tablets and α-interferon nebulization. The stated drug (lopinavir/ritonavir) has the ability to inhibit protease and CYP3A metabolism thus showing antiviral properties (Driggin et al., 2020) (ClinicalTrials.gov; NCT04275388)

Fig. 7.

Structures of isolated compounds and their derivatives from natural products sources in clinical trial studies against COVID-19.

Table. 3.

List of ongoing clinical trials of natural products-based drugs targeting (COVID-19).

Compounds	Natural products origin	Clinical trials/phase/ Type of the study/ No of participants	Dose/ administration route/ Mechanism of action	ReferencesClinicalTrials.govIdentifier
(9-Dehydro-17-hydro-andrographolide (DHA) (78) and sodium 9-dehydro-17-hydro-andrographolide-19-yl sulfate (DHAS) (ND), Xiyanping products (79)	Andrographis paniculata, plant	2019 Novel Coronavirus Pneumonia/ Observational/ 426 P	10–20 ml daily of Xiyanping plus lopinavir tablet or ritonavir tablet plus α-interferon nebulization, For 14 days/ injection	(https://clinicaltrials.gov, NCT04275388)
Chloroquine (S*), alkaloid (27)	Cinchona spp., Plant	COVID19, Coronavirus, Acute Respiratory Illnesses/ Interventional/ 40,000 P	10 mg/kg followed by155 mg daily (250 mg chloroquine phosphate salt or 200 mg of or hydroxychloroquine sulphate)/ for 3 m	(https://clinicaltrials.gov, NCT04303507)
		SARS-CoV, Severe Acute Respiratory Syndrome (SARS) Pneumonia/ Phase 2/ Interventional / 440 P	150 mg/ twice daily/ 10 days	(https://clinicaltrials.gov, NCT04323527)
Fingolimod (ND), Alkaloid (80)	Isaria sinclairii, Fungus	Coronavirus Disease (COVID-19)/ Phase 2/ Interventional/ 30 P	0.5 mg/ once daily, for three consecutive days/ oral / effective agent against COVID-19 via an immunology modulation of phingosine-1-phosphate receptors	(https://clinicaltrials.gov, NCT04280588)
Methylprednisolone (ND), Steroid (81)	Corynebacterium simplex, Bacteria	COVID-19, Novel Coronavirus Pneumonia/ Interventional/ 86 P	1 mg/kg/ day/ for 7 days/ intravenous	(https://clinicaltrials.gov, NCT04273321)
		COVID-19 Infections/ Phase 2/ Interventional/ 80 P	40 mg/ 12 h for 5 days	(https://clinicaltrials.gov, NCT04244591)
Tetrandrine (N), alkaloid (58)	Stephania tetrandra, Plant	Corona Virus Disease 2019,COVID-19/ Phase 4/ Interventional/ 60 P	60 mg QD for 1week	(https://clinicaltrials.gov, NCT04308317)
Tocilizumab (B), Protein (82)	Interleukin-6 (IL-6) receptor antibody, Biological source	Covid-19/ Observational/ 120 P	8 mg/kg / once in 100 ml 0.9% saline solution and administered intravenously within no less than 60 min/ Blocking the inflammatory molecule interleukin-6, decreased systemic inflammation, improved survival rate, better hemodynamic and improved of respiratory distress	(https://clinicaltrials.gov, NCT04306705)

Fingolimod (FTY720) (80), another compound derived from myriocin (ISP-1), is a metabolite of the Isaria sinclairii fungus. Fingolimod has been approved by the regulatory authorities of the US, EU, Australia, and Russia, to treat the relapsing remitting multiple sclerosis. Fingolimod consequently represents the primary oral drug for treatment of this central nervous autoimmune disease (Ingwersen et al., 2012). In China, the Fingolimod drug was tested with 30 patients infected with COVID-19. Every patient was given 0.5 mg of Fingolimod orally daily, for three consecutive days. Fingolimod was used in the current study as an effective agent against COVID-19 acting via an immunology modulation of phingosine-1-phosphate receptors (ClinicalTrials.gov; NCT04280588) (Driggin et al., 2020).

Tetrandrine (58) represents the predominant constituent of the Stephania tetrandra plant, a Chinese traditional medicinal plant. Tetrandrine is bisbenzylisoquinoline alkaloid and recommended in the Chinese Pharmacopoeia as an analgesic and diuretic agent and also for treatment of hypertension and various other ailments like asthma, tuberculosis, dysentery, hyperglycemia, malaria, cancer and fever. It was also used against the Ebola virus infection (Bhagya and Chandrashekar, 2016). In the clinical studies, tetrandrine has been proven effective against COVID-19 via reducing the clinical progress, improving the prognosis, reducing the incidence of pulmonary fibrosis during rehabilitation, and improving patients' quality of life (ClinicalTrials.gov; NCT04308317). Tetrandrine has shown potential in decreasing the entry of SARS-CoV-2 S pseudovirions (Ou et al., 2020). Tocilizumab (82), is a humanized monoclonal antibody that interacts with the interleukin-6 receptor (IL-6R) and is nowadays approved by China's National Health Commission for the treatment of inflammation in patients with COVID-19 (Cron and Chatham, 2020). Previously, Tocilizumab (Actemra®) was permitted by means of the FDA as a drug used for inflammatory bowel disease treatment (Newman and Cragg, 2020). Recently, some physicians in Italy (Pascale Hospital, Naples) claimed that Actemra® (Tocilizumab) succeeded in treating severely ill patients via blocking the inflammatory molecule interleukin-6, decreasing systemic inflammation, improving survival rate, adjusting hemodynamic and relieving the respiratory distress (Day, 2020).

Streptokinase and Heparin were investigated as a treatment for patients infected by Severe Acute Respiratory Syndrome (SARS) and Severe Acute Respiratory Distress Syndrome (ARDS), the first one is an enzyme isolated from the Streptococci bacteria and the other is a glycosaminoglycan derived from dog liver (Anderson et al., 1948; McLean, 1959). The two compounds had been administrated in 40 patients infected with ARDS. The first 20 patients were treated with heparin (10.000 IU) and the other 20 were treated with Streptokinase (250.000 IU). Each drug was prepared in a 3 ml volume of distilled water and nebulized for a period of 15 min every 4 h. The outcome of the study revealed an improvement of the hypoxemia as determined by PaO₂/FiO₂ ratio >100, an improvement of the pulmonary compliance of the patient defined as dynamic compliance >50 ml/cm H₂O, and a decrease of the occurrence of complications such as bleeding or coagulopathy within 72 h of initiation of therapy. Streptokinase and Heparin may prevent /or dissolve intra-alveolar fibrin clots respectively helping alveolar re-expansion (ClinicalTrials.gov; NCT03465085).

Methylprednisolone (81) is a natural products derivative (prednisolone derivative glucocorticoid) implemented by the FDA as an anticancer drug (Feinberg et al., 1957; Hall, 1992; Newman and Cragg, 2020; Ravina, 2011). In early 2020, two clinical studies had been conducted on methylprednisolone against SARS-CoV-2 with 86 and 80 participants respectively. In both studies, all participants recovered except for one case that died in the first study (ClinicalTrials.gov; NCT04273321; NCT04244591).

Chloroquine (27) is a synthetic drug but its pharmacophore is a natural product origin (Quinin isolated from Cinchona spp. plant) (Oliveira et al., 2009), and approved antiphrastic (anti-malaria) drug as per the FDA (Newman and Cragg, 2020). In the 1960′s, it was investigated as an antiviral in vitro for the first time (Touret and de Lamballerie, 2020). Chloroquine was able to inhibit MERS-CoV replication at a very early stage of infection with EC₅₀ of 3.0 µM, and it was reported as a potent anti-viral agent against flavivirus, influenza virus, HIV, Ebola virus, and Nipha-Hendravirus (Pillaiyar et al., 2020). Nevertheless, many clinical studies were conducted on chloroquine as an anti- COVID-19 virus agent (ClinicalTrials.gov; NCT04303507), and its efficacy and safety remain unclear. It is proven highly effective in blocking viral replication in other infections including the SARS-associated coronavirus (CoV) (Cortegiani et al., 2020). However, in a recent observational study, hydroxychloroquine treated patient was more seriously ill than those who hadn't received hydroxychloroquine (Geleris et al., 2020).

Patents of natural products prescriptions against COVID-19 pandemic

As discussed earlier, small-molecule, approved drugs, and natural products are promising entities to combat COVID-19 depending on various mechanisms of action. Traditional Chinese medicine (TCM) has a synergistic effect that plays a vital role in resisting the virus and resisting inflammation of the lung and thus some TCM formulas have been proposed and approved as patents against coronaviruses. Our review devotes to patents from natural product sources (Table 4 ).

Table. 4.

List of patents on the treatment of COVID-19 by using Traditional Chinese Medicine.

Inventor	Ingredients (parts by weight)/ Patent form	Title/ Publication number/ Patent office	Type of virus/ Effective rate or (cure rate)/ Mode of action	References
Chinese name: 葛又文 English name: Ge Youwen	9 parts of ephedra, 6 parts of honey-fried licorice root, 9 parts of almond, 15–30 parts of Gypsum, 9 parts of Cassia Twig, 9 parts of Rhizoma Alismatis, 9 parts of Grifola, 9 parts of bighead Atractylodes rhizome, 15 parts of Poria cocos, 16 parts of Radix Bupleuri, 6 parts of Scutellaria baicalensis, 9 parts of ginger processed Pinellia tuber, 9 parts of ginger, 9 parts of aster, 9 parts of Flos Farae, 9 parts of blackberry lily, 6 parts of Asarum, 12 parts of Chinese yam, 6 parts of immature bitter orange, 6 parts of dried orange peel and 9 parts of wrinkled Gianthyssop herb/ Decoction	Prescription for treating pneumonia caused by novel coronavirus infection and application thereof / (CN110870402A)/ CN	SARS-CoV-2/ 95.12%/ Treating pneumonia	Ge, 2020
Chinese name: 张宁 and 杨海军 English name: Zhang Ning and Yang Haijun	40 parts of Folium Isatidis, 40 parts of the wild Chrysanthemum flower, 20 parts of Coptis chinensis, 30 parts of sweetsop seed, 20 parts of wrinkled Gianthyssop herb, 20 parts of Rhizoma Atractylodis, 20 parts of Radix Bupleuri, 2 parts of Calculus Bovis Factitius, 20 parts of Houttuynia cordata, 5 parts of dandelion root, 30 parts of honeysuckle, 30 parts of Fructus Forsythiae, 20 parts of Scutellaria baicalensis, 20 parts of blackberry lily, 15 parts of Salvia miltiorrhiza, 15 parts of Bulbus Fritillariae Cirrhosae, 10 parts of Saussurea involucrate, 60 parts of Astragalus mongholicus, 20 parts of Cordyceps sinensis, 20 parts of Codonopsis/ Tablet, capsule, granule, pill or oral liquid.	Traditional Chinese medicine composition with function of resisting novel coronavirus SARS-CoV-2 and preparation method and application thereof/ (CN111150792A)/ CN	SARS-CoV-2/ Not reported/ Improve the pneumonia symptom	Zhang and Yang, 2020
Chinese name: 雷鸣 and 养立English name: Lei Ming and Yang Li	33–15 parts of Tripterygium wilfordii, 10–50 parts of Gypsum, 8–24 parts of raw Chinese yam, 5–15 parts of Radix Scrophulariae, 4–12 parts of Fructus Forsythiae, 4–10 parts of Periostracum Cicada, 4–12 parts of Codonopsis pilosula, 3–8 parts of mint, 3–10 parts of burdock and 4–20 parts of raw ochre/ Not reported	Traditional Chinese medicine composition and application thereof/ (CN111184805A)/ CN	SARS-CoV-2/ Not reported/Regulating immunity and utilized to treating SARS-CoV-2	Lei and Yang, 2020
Chinese name: 吴通武, 梁力, 张堂江 and 梁洪海 English name: Wu Tongwu, Liang Li, Zhang Tangjiang and Liang Honghai	15–45 parts of prepared aconite, 10–30 parts of dried ginger, 30–60 parts of honey-fried licorice root, 15–30 parts of American ginseng, 10–30 parts of Ephedra, 15–30 parts of Cassia twig, 5–10 parts of Asarum, 10–70 parts of honeysuckle flower, 10–30 parts of Fructus Forsythiae, 10–30 parts of Isatis root, 10–30 parts of reed rhizome, 15–30 parts of Folium Isatidis, 20–240 parts of Gypsum, 10–30 parts of lalang grass rhizome, 10–15 parts of Rhizoma Paridis, 5–15 parts of wrinkled Gianthyssop herb, 5–10 parts of Eupatorium, 5–10 parts of safflower, 5–15 parts of Cortex Moutan, 5–15 parts of Rheum officinale, 15–45 parts of ginger, 10–30 parts of Chinese date and 5–9 parts of musk/ Liquid	Traditional Chinese medicine formula for treating or preventing novel coronavirus pneumonia and viral influenza/ (CN111110819A)/ CN	SARS-CoV-2/(80%)/ Improving human immunity and prevention or treatment of SARS-CoV-2	Wu et al., 2020
Chinese name: 潘耀宗, 王恒斌, 张丹丹, 张邦国, 李全, 罗年翠, 曹泽庆 and 翟云良 English name: Pan Yaozong, Wang Hengbin, Zhang Dandan, Zhang Bangguo, Li Quan, Luo Niancui, Cao Zeqing and Zhai Yunliang	40 parts of wrinkled Gianthyssop herb, 40 parts of wild Chrysanthemum flower, 24 parts of Chinese mosla herb and 40 parts of sweet wormwood herb/ Tablets, capsules, pills, oral liquid, or mixtures.	Chinese medicine composition for preventing and treating viral diseases and application thereof/ (CN111150755A)/ CN	SARS-CoV-2/Not reported/ Inhibiting cytokine expression i.e. TNF- α and IL-6 produced by SARS-CoV-2	Pan et al., 2020a
Chinese name: 王学昌, 张董喆 and 程少丹 English name: Wang xuechang, Zhang Dongzhe and Cheng Shaodan	50–80 parts of clove, 20–30 parts of Cacumen Biotae and 15–20 parts of Angelica dahurica; 10–15 parts of honeysuckle; 10–15 parts of Agastache rugosus, 10–15 parts of Eupatorium fortunei, 10–15 parts of Cassia twig, 10–15 parts of camphor, 10–15 parts of Saposhnikovia divaricate root, 10–15 parts of isatis root, 10–15 parts of folium Artemisiae argyi and 10–15 parts of borneol/ Capsule	Sachet for efficiently preventing novel coronavirus pneumonia and influenza/ (CN111214689A)/ CN	SARS-CoV-2/ Not reported/ Preventing novel coronavirus pneumonia and preventing and treating respiratory diseases	Wang et al., 2020a
Chinese name: 张涛涛, 何莉华 and 彭严 English name: Zhang Taotao, He Lihua and Peng Yan	3–18 parts of Ephedra, 2–10 parts of liquorice, 3–18 parts of almond, 5–45 parts of Gypsum (decocted first), 3–18 parts of Cassia twig, 3–18 parts of Rhizoma Alismatis, 3–18 parts of Grifola, 3–18 parts of bighead Atractylodes rhizome, 5–25 parts of Poria cocos, 6–26 parts of Radix Bupleuri, 2–10 parts of Scutellaria baicalensis, 3–18 parts of ginger Pinellia ternata, 3–18 parts of ginger, 3–18 parts of aster, 3–18 parts of Flos Farfarae, 3–18 parts of blackberry lily, 2–10 parts of Asarum, 6–18 parts of Chinese yam, 2–10 parts of immature bitter orange, 2–10 parts of dried orange peel, 2–10 parts of Rhizoma Atractylodis, and the like, 3–18 parts of Agastache rugosus/ Tablets, powder, soft capsules, syrup, pills and granules.	Traditional Chinese medicine composition and preparation method and pharmaceutical application thereof/ (CN111214637A)/ CN	SARS-CoV-2/ Not reported/ Treating or preventing the new coronavirus 2019-nCoV	Zhang et al., 2020
Chinese name: 奚肇庆, 束雅春, 刘志辉, 马朝群, 汪悦, 史锁芳, 乔飞, 吴磊 and 吴旭彤 English name: Xi Zhaoqing, Shu Yachun, Liu Zhihui, Ma Chaoqun, Wang Yue, Shi Suofang, Qiao Fei, Wu Lei and Wu Xutong	6–30 parts of Astragalus membranaceus, 6–30 parts of Codonopsis pilosula, 5–18 parts of bran-fried bighead Atractylodes rhizome, 6–15 parts of Poria cocos, 3–30 parts of Perilla leaf, 3–15 parts of Saposhnikovia divaricata root, 3–20 parts of dried orange peel, 2–15 parts of Chinese date and 2–9 parts of liquorice/ Extract, granules, capsules or pills	Epidemic prevention traditional Chinese medicine composition and preparation method and application thereof/ (CN111214566A)/ CN	SARS-CoV-2/ Not reported/ Prevent the infection of the new coronavirus SARS-CoV-2	Xi et al., 2020
Chinese name: 杨汉梅, 陈彩虹,陈天跃 and 杨仪鏐 English name: Yang Hanmei, Chen Caihong, Chen Tianyue and Yang Yiliao	8–12 parts of semiliquidambar cathayensis, 8–12 parts of cinnamomum camphora root, 8–12 parts of citronella, 8–12 parts of Sculellaria barbata, 8–12 parts of giant knotweed rhizome, 8–12 parts of honeysuckle stem, 8–12 parts of weeping forsythia, 8–12 parts of dandelion, 8–12 parts of radix bupleuri, 8–12 parts of Cnanchum glaucescens, 8–12 parts of bitter apricot kernel, 8–12 parts of aster, 8–12 parts of reed rhizome and 8–12 parts of euphorbia lathyrism/ Pills	Fumigation bath preparation for preventing and treating pestilence, and its application method and application/ (CN111184823A)/ CN	SARS-CoV-2/ 90% (80%)/ Improve human immunity and has prevention and treatment effects on new coronavirus pneumonia	Yang et al., 2020a
Chinese name: 陈文才 English name: Chen Wencai	20–100 g of Laggera pterodonta, 10–50 g of honeysuckle, 10–30 g of dried ginger, 10–40 g of divaricate saposhnikovia root, 10–50 g of Officinal magnolia bark and 10–60 g of pilose asiabell root/ liquid	Laggera pterodonta composition for treating new COVID-19 and application thereof/ (CN111166862A)/ CN	SARS-CoV-2/ Not reported/ Preventing and treating infectious plague and common respiratory diseases, resisting virus and enhancing immunity	Chen, 2020

One prescription for treating pneumonia caused by the new coronavirus infection was inspired by the TCM composition and discloses. The prescription raw materials combine, parts by weight, of the following TCM materials: 9 parts of Ephedra, 6 parts of honey-fried licorice root, 9 parts of almond, 15–30 parts of Gypsum, 9 parts of Cassia Twig, 9 parts of Rhizoma Alismatis, 9 parts of Frifola, 9 parts of bighead Atractylodes rhizome, 15 parts of Poria cocos, 16 parts of Radix Bupleuri, 6 parts of Scutellaria baicalensis, 9 parts of ginger processed Pinellia tuber, 9 parts of ginger, 9 parts of aster, 9 parts of Flos Farae, 9 parts of Blackberry lily, 6 parts of Asarum, 12 parts of Chinese yam, 6 parts of immature bitter orange, 6 parts of dried orange peel and 9 parts of wrinkled Gianthyssop herb. The effective rate of treatment was reported to 95%. The percent of effective rates was calculated based on the number of confirmed diagnosis and the number of treated patients from different places. This patent was documented in patent office CN with publication number (CN110870402A) (Ge, 2020).

Another TCM prescription is composed of the following raw materials in parts by weight: 40 parts of Folium isatidis, 40 parts of the wild Chrysanthemum flower, 20 parts of Coptis chinensis, 30 parts of sweetsop seed, 20 parts of wrinkled Gianthyssop herb, 20 parts of Rhizoma Atractylodis, 20 parts of Radix Bupleuri, 2 parts of Calculus Bovis Factitius, 20 parts of Houttuynia cordata, 5 parts of dandelion root, 30 parts of honeysuckle, 30 parts of Fructus Forsythiae, 20 parts of Scutellaria baicalensis, 20 parts of blackberry lily, 15 parts of Salvia miltiorrhiza, 15 parts of Bulbus Fritillariae Cirrhosae, 10 parts of Saussurea involucrate, 60 parts of Astragalus mongholicus, 20 parts of Cordyceps sinensis, 20 parts of Codonopsis. Observation of clinical experiments shows that the patent boosted the pneumonia symptoms caused by the new SARS-CoV-2 coronavirus. This patent was documented in patent office CN with publication number (CN111150792A) (Zhang and Yang, 2020).

Tripterygium wilfordii is the main formula for one of the TCM patents. The composition of this patent has the following raw materials as parts by weight: 3–15 parts of Tripterygium wilfordii, 10–50 parts of Gypsum, 8–24 parts of raw Chinese yam, 5–15 parts of Radix Scrophulariae, 4–12 parts of Fructus Forsythiae, 4–10 parts of Periostracum cicada, 4–12 parts of Codonopsis pilosula, 3–8 parts of mint, 3–10 parts of burdock and 4–20 parts of raw ochre. This patent was claimed suitable for the severe stage of COVID-19 pneumonia diseases, regulating immunity and decreasing the fever. The administration rate of the prescription (3–5 times) can decrease body temperature to the normal range. Tripterygium wilfordii relates to Chinese herbal medicine, and used in traditional medicine for promoting blood circulation, killing parasites, regulating immunity, and has a good medicinal effect when utilized in treating 2019 new coronavirus pneumonia. This patent was documented in patent office CN with publication number (CN111184805A) (Lei and Yang, 2020).

One more patent that also relates to TCM, is possessing a formula for treating or preventing both novel coronavirus pneumonia and viral influenza. This formula combines raw materials, parts by weight, as a following: 15–45 parts of prepared aconite, 10–30 parts of dried ginger, 30–60 parts of honey-fried licorice root, 15–30 parts of American ginseng, 10–30 parts of Ephedra, 15–30 parts of Cassia twig, 5–10 parts of Asarum, 10–70 parts of honeysuckle flower, 10–30 parts of Fructus Forsythiae, 10–30 parts of Isatis root, 10–30 parts of reed rhizome, 15–30 parts of Folium Isatidis, 20–240 parts of Gypsum, 10–30 parts of lalang grass rhizome, 10–15 parts of Rhizoma Paridis, 5–15 parts of wrinkled Gianthyssop herb, 5–10 parts of Eupatorium, 5–10 parts of safflower, 5–15 parts of Cortex Moutan, 5–15 parts of Rheum officinale, 15–45 parts of ginger, 10–30 parts of Chinese date and 5–9 parts of musk. This patent has a corollary effect on ventilating lungs and improving human immunity. It was used for coronavirus, influenza, and pneumonia prevention or treatment. The findings showed that 24 patients out of 30 were cured and that this formula was helpful in treating the new coronavirus pneumonia effectively. The cure rate was estimated to 80%. This patent was documented in patent office CN with publication number (CN111110819A) (Wu et al., 2020).

Another formula was studied in vitro against common coronavirus and new coronavirus. The formula composed of the following raw materials, as parts by weight: 40 parts of wrinkled Gianthyssop herb, 40 parts of wild Chrysanthemum flower, 24 parts of Chinese mosla herb and 40 parts of sweet wormwood herb. This formula has a potent effect on inhibiting cytokine expression i.e. TNF- α and IL-6 produced by SARS-Cov-2. The formula was used earlier as a therapeutic agent against pneumonia, nephritis, hepatitis. It has very good prospects for clinical application and thus it was approved from CN patent office under publication number (CN111150755A) (Pan et al., 2020a).

The protective role of plants and their constituents against COVID-19

The consumption of healthy diets is one way to boost the immune system and in return help in fighting off viruses (Galanakis, 2020). There is a wide range of plants that contribute to boosting the immune system given their high content of a wide variety of nutrients and biological active compounds (Sultan et al., 2014). A strong immune system is essential for fighting against COVID-19. COVID-19 seems to be hazardous for people with comorbidities and those have a weaker immune system than healthy ones (Chen et al., 2020b; Jiang et al., 2020). Garlic stimulates the immune system as it is rich with a wide plethora of nutrients, vitamins, and sulfur-containing compounds (Iciek et al., 2009). Certain vegetables such as broccoli, spinach and sweet potatoes are abundant with vitamin A which include retinol, retinoic acid and β-carotene. These fat-soluble compounds participate in enhancement of the immune function. Additionally, isotretinoin (vitamin A derivative), inhibits ACE2 and the entry of SARS-COV-2 into the body thereby lower the susceptibility to infections (Galanakis, 2020). Citrus fruits are one of the best sources for vitamin C. Vitamin C increases the production of white blood cells providing a key role in fighting infections (Calder et al., 2020). Vitamins are recommended for the protection against coronavirus as they increase patients' resistance against infection (Basiri, 2020).

Conclusions

The outbreak of COVID-19 has swept across the world rapidly spreading in a very alarming pace invading more than 200 countries, territories, areas leaving a trail of victims behind. Although SARS-CoV-2 is accompanied by symptoms similar to that of SARS-CoV-2 i.e. fever, cough, and fatigue, SARS-CoV-2 is far more contagious. It can be transmitted by droplets or close contact. Given the affinity by which SARS-CoV-2 protein S can bind to ACE2 receptors, human to human transmission seems to spread much faster than the common flu or even the previous coronaviruses. Thus, containing the outbreak is a burning issue requires extensive measures and developing specific safe drugs. Natural products have so far proven to be promising for the development of effective and less toxic antiviral agents. Owing to the genetic resemblance between coronaviruses, the drugs and antiviral agents which are usually effective against the other types of coronaviruses could be used to treat COVID-19. Some of the reported antivirals showed a promising antiviral activity against at least four types of human coronaviruses with significant EC₅₀ and CC₅₀ values. Other therapeutic agents have also been reported and are already moving into clinical trials including Xiyanping, fingolimod, methylprednisolone, streptokinase, and heparin.

Funding

This work was supported by the Swedish Research Council Vetenskapsrådet (grants 2015‐05468 and 2016‐05885)

Declaration of Competing Interest

The authors declare no conflict of interest.