Phytochemicals candidates as promising preventives and/or curatives for COVID-19 Infection:

1Laboratory of Biochemistry and Molecular Biology, University of Carthage, Faculty of Sciences of Bizerte, CP 7021-Jarzouna, Tunisia 2Laboratory of Hetero-Organic Compounds and Nanostructured Materials, University of Carthage, Faculty of Sciences of Bizerte, CP 7021-Jarzouna, Tunisia 3Laboratory of Bioactive Molecules and Applications, Department of Applied Biology, University of Tebessa, Tebessa, Algeria More Information


Introduction
A new severe pandemic pneumonia generated from a large seafood and animal market in the city of Wuhan (China) on December 2019 killed thousands of people around the world [1].
As of May 10, 2020, 61,165 cases con irmed and 2,239 deaths have been reported in Africa [2]. The spread out of this pandemic in Africa raise fears of the worst. In terms of healthcare, these countries face a large number of challenges, including lack of funds and poor infrastructures [3]. Besides, the availability of the vaccine or drug, if there is, will not be accessible to all layers of society.
Human coronavirus disease (COVID-19 or SARS-CoV-2) presents a severe acute respiratory, fever, dry cough, shortness of breath, fatigue and decreases of white blood cells and kidneys function. SARS-CoV-2 is an enveloped virus, classi ied in the beta-corona viruses group with a single-stranded positive-sense RNA genome and high nucleotide similarity (89%) with SARS coronavirus (SARS-CoV) genes [4]. The viral 3-chymotrypsin-like cysteine protease is the major protease produced by the SARS-CoV-2 that plays a key role in the production of functional viral proteins, which maintains the virus replication [5]. This protease shares 96% of similarity with SARS coronavirus protease [6]. Studies showed that the receptor-binding domain of COVID-19 strongly interacts with type I integral membrane human protein ACE2, where it is easily able to enter the host cells [7]. Treatment of COVID-19 remains a big challenge and more attention due to (i) the adaptation of virus, (ii) the resistance of SARS-CoV-2 to antiviral drugs and (iii) the possible development of new viral and bacterial strains [1].
Currently, SARS-CoV-2 is treated using chloroquine and hydroxychloroquine knowing for their ability to inhibit the SARS coronavirus and to treat HIV infections [8]. Scientists believed that both drugs can inhibit the ACE2 protein, but their risk of toxicity and side effects is of great concern [8].
For decades, medicinal plants have gained wide popularity due to their bene icial effect in treating various diseases. All civilizations around the globe offer unlimited sources of traditional plants and herbs that provide numerous phytochemicals compounds used in pharmaceutical industry. Meanwhile, over than 40% of natural products have been used in the synthesis of pharmaceutical drugs [9]. Virtually, the use of medicinal plants or their phytochemicals have gained an attractive interest to prevent and to treat the viral infections. It was well established that the main antiviral mechanisms of natural compounds are the inhibition of viral replication, assembly of intracellular particles, RNA polymerase, viral neuraminidase, protease, reverse transcriptase and viral protein expression [10]. As well as, many traditional medicinal plants have shown promising results in treating the coronavirus as shown in igure 1 [11][12][13]. Moreover, phytochemicals compounds have shown their direct antiviral impact and their ability to biosynthesis nanoparticles with promising antiviral activity [1,14,15]. These facts can be attractive to develop effective drugs much safer than chemical drugs. This brief-review will provide information on the most effective medicinal plants in the treatment of coronavirus, as well as the mechanism in silico of their phytochemicals compounds against SARS-CoV-2 infection.

Methodology
Literatures were collected from the online bibliographical databases: PubMed, Scopus, Google Scholar, and Web of Sciences. The following keywords were used to search recent papers: "anti-coronavirus", "antiviral activity", "medicinal plants", "COVID-19", "phytochemical compounds", "bioactive compounds", "anti-SARS activity", "anti-HIV", and "Anti-HSV". In this brief review, we cited forty-three papers that are tightly correlated with the main objective of this work.

Olea europaea L [Olive]
Olea europaea is among the oldest trees grown in the world known by its therapeutic properties. The bioactive compounds extracted from Olea europaea fruits such as oleuropein, apigenin-7-glucoside, and luteolin-7-glucoside showed a potential inhibition of SARS-CoV-2 infection pathway through blocking the 3-chymotrypsin-like cysteine protease [6].

Glycyrrhiza glabra [Liquorice]
Liquorice has been used clinically for centuries in several therapeutic applications. The glycyrrhizin (Figure 3), bioactive substance extracted from liquorice plant, showed a clinical anti SARS-CoV activity by affecting the cellular signalling pathways like protein kinase C, casein kinase II, and nuclear factor in SARS-CoV [11].
Natural compounds of Baikal skullcap (Figure 2), such as scutellarein has showed potent inhibition of SARS-CoV helicase by affecting the activity of ATPase [19]. Besides, the scutellarin compound was revealed as promising agent to prevent SARS-CoV-2 infection by inhibiting ACE2 [1].

Lycoris radiate [Red spider lily]
Li, et al. [20] reported that the stem cortex of the Lycoris radiata herbs has potent antiviral activities against coronavirus (SARS-CoV) at a concentration of 15.7 nM. These results indicate that lycorine may be an alternative candidate to prevent or treat SARS-CoV-2 infection, since it shared similarity with the SARS virus (Table 1).

Allium sativum [Garlic]
The garlic is widely consumed due to its bioactive compounds richness. As show in igure 3, allicin is one of the most bioactive compounds with high activity against SARS-CoV-2 through the inhibition of 3-chymotrypsin-like cysteine protease [6].

Isatis indigotica [Woad]
The anti-SARS coronavirus activity was investigated by using Isatis indigotica root extract and plant-derived phenolic compounds. It showed that hesperetin from this plant inhibited the 3-chymotrypsin-like cysteine protease, which blocks the coronas virus [16].

Houttuynia cordata Thunb [Saururaceae]
The Houttuynia cordata (Saururaceae) is widely used in Chinese medicine to treat SARS disease. The saururaceae extract proved a varied inhibitory effect on SARS coronavirus 3-chymotrypsin-like cysteine protease and RNA-dependent RNA polymerase [21].

Ligustrum lucidum [Broad-leaf privet]
Phytochemicals isolated from Ligustrum lucidum fruits known by their richness of bioactive compounds. Of particular interest, specnuezhenide and neonuezhenide, which belong to secoiridiod glycosides class. These compounds have showed potent inhibitory activity against 3-chymotrypsin-like cysteine protease through binding to conventional hydrogen bonds, carbon hydrogen bonds, van der Waals force, and hydrophobic interaction [5].

Zingiber of icinale [Ginger]
Ginger is frequently used in food and traditional medicine. Bioactive compounds from ginger, such as zingerol and gingerol (Figure 2), have shown an inhibition of 3-chymotrypsin-like cysteine protease in SARS-CoV-2 infection [6].
Moreover, from a biological and pharmacological point of view, it is very important to note the vital activity of the

Torreya nucifera [Japanese torreya]
Torreya nucifera is an ancient tree used for decades in traditional Asian medicine. The ethanol extract of T. nucifera leaves exhibited good activity against SARS coronavirus. Three bio lavonoids from T. nucifera (apigenin, luteolin, and quercetin) have demonstrated a potential inhibitory activity of 3-chymotrypsin-like cysteine protease [22].

Cupressus sempervirens L [Cypress]
The hydro-ethanolic extract from fresh cones of cypress (Cupressus sempervirens L) has been tested against Corona VR-740. The study revealed a massive amount of bioactive molecules in cypress extract, such as catechin, epicatechin, tannins of proanthocyanidin, and lavonoids that inhibited the coronavirus activity within 60 min [23].

Laurus nobilis [Bay tree]
The essential oil of Laurus nobilis berries was also found to be potent against corona viruses. The presence of ß-ocimene and 1.8-cineole in sweet bay berries oil gave an interesting anti SARS-CoV activity [24].

Crocus Sativus L [Saffron crocus]
The lower of saffron crocus contains considerable amount of natural bioactive compounds like crocin, which is known as anti-HSV (Herpes simplex virus) and anti-HIV (human immunode iciency viruses) agents (Table 1) [25,26]. A recent study revealed that crocin demonstrated good interaction with the receptor of SARS-CoV-2, similar to chloroquine [25]. 16. Phytochemical compounds as Anti-SARS-CoV-2 3-chymotrypsin-like cysteine protease [6,42] avarol molecule extracted from marine sponge Dysidea avara Schmidt in some pharmacological effects such as HIVlike infections [29]. The derivatives of this molecule can also inhibit acetyl cholinesterase activity and could be a promising in neurodegenerative disorders such as Alzheimer's disease [30 ].

Conclusion
The current review summarized the principal medicinal plants and their phytochemicals compounds that have been screened in silico as promising preventive and curative candidate against SARS-CoV-2 infection. While, lavonoids showed the most potent activity. The main target sites of these compounds are the inhibition of 3-chymotrypsin-like cysteine protease, ACE2 protein, and viral replication. Overall, it is necessary to conduct further investigations to verify the in vivo potentiality of these phytochemicals compounds on SARS-CoV-2 infection. As well as, the interest should be taken on the use of bio-nanomaterials to bene it from the precise and high effect of the bioactive molecule.

Author contributions
SH, NJ, and RH were responsible for the writing of the manuscript. AL corrected the manuscript. AC designed, corrected, and approved the manuscript.