**Abstract**

World Health Organization (WHO) declared on March 11, 2020, coronavirus disease, which erupted in December 19th, 2019 in Wuhan, China (COVID-19) as worldwide pandemic disease. Researchers worldwide were successful to provide a prophylactic approach *via* developing several vaccines, which were swiftly approved by WHO under Emergency Use Listing (EUL) status. So far, lopinavir, chloroquine, azithromycin, hydroxychloroquine, favipiravir, umifenovir, ribavirin, remdesivir, and darunavir have been tested clinically. Hydroxychloroquine, favipiravir, and chloroquine exhibited a high ratio of distribution for the lung and were reported to minimize viral tonnage in respiratory system of many COVID-19 cases. However, none of the tested drugs showed a conclusive, safe, and efficient activity against COVID-19. This prompted many experts in drug discovery to fetch in the treasure of many available old drugs of natural origin to repurpose based upon their well-studied pharmacology, pharmacodynamics, virtual screening, and artificial intelligence studies. In this review chapter, we will address the repurposing of natural products and their derivatives to be used in treatment of COVID-19 *via* targeting host cells machinery and viral proteins either in early stages by blocking virus entry to cells or lately through inhibition of viral replication.

**Keywords:** COVID-19, inflammation, viral replication, drug repurposing, artificial intelligence, natural products

## **1. Introduction**

SARS-CoV-2 is a relatively large virus with single-stranded RNA genome, belongs to beta coronaviruses that affects the lower respiratory system to cause viral pneumonia. The gastrointestinal system, kidney, heart, liver, and central nervous system may also be attacked leading to multiple organ failure. It is surrounded by an envelope composed of a lipid bilayer and envelope proteins [1].

#### **1.1 The life cycle of COVID-19**

The COVID-19 viral infection is mediated by three main stages: the first one involves host cell entry through endocytosis and transportation proteins; the second stage initiates viral RNA translation to polyprotein, which is subjected to cleavage by the main viral proteinases Mpro and Papain-like proteases PLpro to produce the effector proteins; in the final stage, the negative-strand viral RNA is translocated to the Golgi apparatus to produce new virions, and the newly produced virus are released by exocytosis [1].

#### **1.2 Host cell viral entry and nuclear translocation**

The viral entry was found to be mediated by endocytic pathways, which is initiated by the binding of spike protein (S protein), a protein found on the envelope of the virus, to a receptor protein located on the host cell surface membrane, known as angiotensin-converting enzyme 2 (ACE2). The S protein is cleaved into S1 and S2 by a human cell-derived protease that is assumed to be Furin. S1 then binds to its receptor, ACE2. The other fragment, S2, is cleaved by TMPRSS2, a serine protease. Thus, ACE2 and TMPRSS2 are essential in airway cells for SARS-CoV-2 infection [2].

Also the viral entry was found to be facilitated through endocytosis [3], especially clathrin-mediated endocytosis (CME) helps in translocation of ACE-2/virus complex to endosome where the virus is uncoated by the action of acidic proteases such as cathepsins, which are cysteine proteases in host cells involved in facilitating viral entry of several viruses such as SARS-COV and MERS-COV [4]. It's worthy to note that cathepsins are also involved in S protein cleavage [5, 6].

After uncoating, the viral RNA expression and replication require subcellular localization of viral and cellular proteins from cytoplasm to the nucleus. The viral infection induces the translocation and expression of group of suprafamily protein in the host cells called karyopherin, Importins (IMP) α/β heterodimer. These proteins are reported to be utilized by the virus not only for translocation purposes, but also for disruption of self-antiviral defenses in response to interferon via intervening with the nuclear import of signal transducer and activator of transcription proteins (STAT). Chromosome Region Maintenance-1 (CRM1) is one of those proteins that contribute significantly in nuclear export of viral protein and RNA in wide range of viruses [7].

#### **1.3 Translation of viral RNA to nonstructural protein**

The SARS-Cov-2 genome has a large replicase gene, which contains nonstructural proteins (NSPs), structural proteins, and accessory genes. The replicase gene encodes two open reading frames (ORFs) after frameshifting, translated into two large polyproteins pp1a and pp1ab, then processed by two viral proteases: papain-like protease (PLpro, encoded within Nsp3) and Mpro aslo called 3C-like protease (3CLpro, encoded by Nsp5) to produce 16 viral Nsps that their function has been linked to RNA replication. PLpro is believed to play important role to protect the virus from immune response by inactivating ubiquitindependent cellular responses to viral infection and blocking of cytokine production [8, 9].

#### **1.4 Genome replication and production of new viruses**

After cell invasion, a full-length negative-strand RNA template is synthesized by nonstructural protein 12 (Nsp12) RNA-dependent RNA polymerase (RdRp) to produce more viral genomic RNA [10].

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

Another important nonstructural protein is RNA helicase, which has main role in the replication of viruses by catalyze unwinding of double-stranded RNA. It is structurally conserved among different types of viruses, thereby making it an excellent target for development of broad-spectrum antiviral agents [11, 12].

#### **1.5 Translation of structural protein virion assembly and release**

In this stage, the viral RNA is translocated to endoplasmic reticulum (ER) where it is translated to transmembrane structural proteins (S, HE, M, and E) and some membrane-associated accessory proteins, except for the N protein, which is translated by free ribosomes in the cytoplasm [13]. These structural proteins play the main role in virion morphogenesis and the structural components recruitment to the proper assembly site. Then they are released from the cell by exocytosis by the help of several host factors [14].

However, in the COVID-19 pandemic, an integrated approach encompassing prophylaxis, diagnosis, and treatment must be adopted worldwide.

#### **2. Approaches for prophylaxis, diagnosis, and therapy**

Among the top priorities for regulating and monitoring COVID-19 are:

1.An appropriate prophylactic procedure (vaccination).

2.Accurate diagnostic battery.

3.An unambiguous therapeutic regimen.

#### **2.1 An appropriate prophylactic procedure (vaccination)**

WHO stated that "vaccine must supply a quite convenient beneficial environment for dealing with jeopardy; with high performance, only passing with mild effects and with no danger effects." The vaccine should be appropriate for lactating, gravid women and for all ages and has many production sources dwell in high-, middle-, and low-income countries [15]. There is a race among several pharmaceutical companies to provide a treatment for COVID-19. Unfortunately, this completion had led to a big controversy, which was refuted by WHO issued on 20 November 2020 "there is a conditional recommendation against the use of remdesivir since there isn't enough evidence to support its use." Moreover, WHO has issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients (https://www.who.int/news-room/feature-stories/detail/ who-recommends-against-the-use-of-remdesivir-in-covid-19-patients).

However, by the end of 2020 (exactly December 2020), Pfizer/BioNTech was able to get an Emergency Use Listing approval (EUL) for vaccine against COVID-19. Currently and as reported by on January 20th, 2022, nine vaccines were granted EUL status [16, 17].

• The Pfizer/BioNTech Comirnaty vaccine, 31 December 2020.

