*2.4.1.1.4.2 Chromosomal maintenance 1 (CRM-1 also known as exportin 1 (XPO1)) inhibition*

Finally, leptomycin B (LMB), a compound isolated from *Streptomyces* sp, with prominent anticancer and anti-inflammatory activity, which is attributed to its ability to block CRM-1. While the main research focus of this target was on its role in tumorigenesis; it's now known that it contributes in the infection of different viruses. There are a lot of natural compounds reported to target CRM-1 such as valtrate, which is anxiolytic compound isolated from valerian roots, acetoxychavicol, curcumin, goniothalamin, piperlongumine, and plumbagin. These compounds share the presence of alpha, beta unsaturated ketone, making structure similarly to LMB, which seems to be important feature to interact with Cys528 via Michael-type addition and exert their inhibitory actions. Despite the reported antiviral activity of these molecules, there are

*Perspective Chapter: Repurposing Natural Products to Target COVID-19 – Molecular Targets... DOI: http://dx.doi.org/10.5772/intechopen.103153*

#### **Figure 4.**

*Chemical structure of compounds that inhibit endocytic pathway and translocation mechanisms.*

no studies addressing this effect in COVID-19. **Figure 4** shows the chemical structure of compounds that inhibit endocytic pathway and translocation mechanisms.

#### *2.4.1.2 Inhibition of nonstructural proteins formation*

We have addressed the role of host cells factor and protein inhibition in controlling viral infection. So, we will focus mainly on some important targets of the virus itself. The proteolysis of polypeptide to the 16 NSp is a rate-limiting step in viral replication; thus, it is obvious that targeting viral proteases could achieve significant antiviral activity.

#### *2.4.1.2.1 Inhibition of SARS-CoV-2 main protease (Mpro, also called 3CLpro)*

Mpro is one of the best characterized drug targets among coronaviruses. This enzyme is essential for processing the translated polyproteins from the viral RNA. The Mpro works at not less than 11 cleavage sites on the large polyprotein 1ab (replicase 1ab, ~790 kDa); the recognition sequence at most sites is Leu-Gln↓(Ser,Ala,Gly).

The viral replication could be blocked by Mpro inhibitors [65–67]. There are no human proteases with a similar cleavage specificity. Therefore, these inhibitors are not supposed to be toxic. Peptidomimetic alpha keto-amides were reported to be potential Mpro inhibitors [68]. The natural α-keto amides such as eurystatin A and B, complestatin, and aplidine display prolyl endopeptidase inhibitor, HIV replication inhibitor, and antitumor activity, respectively [68]. Also, theaflavin-3,3′-digallate was reported as natural protease inhibitor in SARS-CoV [9]. Other flavonoids are reported to strongly block Mpro activity such as pectolinarin, rhoifolin, herbacetin [69].

### *2.4.1.2.2 Inhibition of SARS-CoV-2 papain-like protease (PLpro)*

PLpro has dual function, beside its role in release of other nonstructural protein, it neutralizes the immune response by the host cell due its deubiquitinating activity, so its inhibition will not only stop the replication cascade but will help the immune system to regain the ability to recognize and destroy the virus [70, 71]. Hirsutenone, a diarylheptanoid from *Alnus Japonica*, was able to inhibit Plpro in uncompetitive manner at IC50 = 4.1 μM, which was attributed to the presence of catechol ring and alphabeta unsaturated ketone [72]. Also tanshinone IIA achieved significant inhibition at IC50 = 0.8 μM, the binding of this compound with PLpro was noticed to increase with time indicating the possibility of covalent bond inhibition [73]. Tomentin E geranylated flavonoid was discovered to be mixed-type inhibitor of this target by bio-guided isolation, its IC50 = 5.0 μM. The inhibition assay demonstrated that flavonoid bearing dihydropyran ring might be superior inhibitor in comparison to parent compounds. **Figure 5** shows chemical structure of SARS-COV proteases inhibitor from natural products [74].

#### *2.4.1.3 Inhibition of viral replication*

After the transcription of viral RNA to the required structural protein, the hijack of the host cell continues to make many replicas of the viral RNA that will be packed

**Figure 5.**

*Chemical structure of natural compounds that inhibit viral proteases (Mpro and PLpro).*

*Perspective Chapter: Repurposing Natural Products to Target COVID-19 – Molecular Targets... DOI: http://dx.doi.org/10.5772/intechopen.103153*

and released. The new virus, RNA helicase was found to be crucial to viral genome replication, which explains why it is a potential target for antiviral drug development. Scutellarin inhibits 90% of SARS-COV RNA helicase activity at 10 μM probably by binding to the ADP active site, myricetin showed the same activity but with much lower extent [75]. Interestingly, ivermectin has shown the ability to inhibit RNA helicase of flavivirus [76], taking in consideration that helicase are structurally conservative among most of the viruses. Ivermectin might also be able to exert the same activity in COVID-19, which in fact may explain the potent antiviral activity addressed previously. **Figure 6** shows the chemical structure of the natural helicase inhibitor.

#### *2.4.1.4 The role of natural products in immunity modulation and alleviation of inflammation associated with COVID-19*

One of the hallmarks of late-phase COVID-19 infection is uncontrolled intense release of proinflammatory mediators, which is known as cytokines storm. Different types of viruses tend to activate mitogen-activated protein kinase (MAPKs) cascades, which control proliferation and inflammation in order to stimulate the replication process of the virus RNA. Since the upregulation of MAPKs was linked to several inflammatory and autoimmune diseases, it can lead to multiorgan failure and potentially death.

Clinically, in some patients, it has been reported that their immune response to the SARS-CoV-2 virus results in the increase of cytokines IL-6 and IL-10 [77].

Both hydroxychloroquine and chloroquine have immunomodulatory effects and can suppress the increase of immune factors. Bearing this in mind, it is possible that early treatment with either of the drugs may help prevent the progression of the disease to a critical, life-threatening state. In critically ill SARS-CoV-2-infected patients, the use of corticosteroids may be harmful. While the use of immunosuppressants (e.g., tocilizumab) is not ideal either as it can suppress the immune system and lead to an increased risk of infection. In this setting, hydroxychloroquine may be an ideal drug to treat SARS-CoV-2 infection as it can inhibit the virus via its antiviral effects and help mediate the cytokine storm via its immunomodulatory effects [78].

Fortunately, natural products could serve as the perfect solution in such case as they would not only work as antiviral agents but also could help to downregulate proinflammatory gene and protein expression via affecting a plethora of MAPKs and transcriptional factors. LPS-induced expression of proinflammatory cytokine could be considered as an excellent model for screening, since LPS also activates the inflammatory mediators through several pathways.

For example, diarylheptanoids, flavonoids, and triterpenes, which possess antiviral activity as mentioned earlier, were able to suppress the gene expression of TNF-alpha,

**Figure 6.** *Chemical structure of the natural helicase inhibitors.*

#### **Figure 7.**

*Chemical structures for the potential natural immunomodulators for cytokine storm associated with COVID-19 infection.*

IL-1β, IL-6 in different types of cells such as macrophages and HepG2 induced by LPS by modulating multiple intracellular signaling pathways in macrophages and prevent LPS-induced IL-6 production by reducing the mRNA stability via inhibiting ERK1/2 activation. This could be achieved by natural compounds such as flavokawain A, curcumin, quercetin curculigoside, syringic acid or vanillic acid, licochalcone A, chrysin, apigenin, and luteolin at transcriptional level [78, 79]. In brief, the anti-inflammatory effect of natural products is so prominent to be summarized in this chapter, and they can contribute significantly at reducing the mortality rates associated with COVID-19 complications (**Figure 7**).
