**1. Introduction**

The challenge of the epidemic outbreak has reached alarming levels, shocking national healthcare systems to unpreparedness and causing international deployment. No drug therapy has been found to be effective in the treatment of the virus, despite COVID-19 being declared a global pandemic by the World Health Organization (WHO). In contrast, several randomized controlled trials conducted towards treatment have not yet provided practical guidance on therapeutic choices and pharmacologic therapy. Several successful research tests for therapy are currently underway. Other emerging, non-conventional drug discovery approaches include alternative ways to discover potent anti-SARS-CoV2 drugs that are quicker and less expensive. In addition, while drugs for COVID-19 are being repurposed and discovered, new drug delivery systems will play a major role in developing

effective delivery systems that have the potential to attack viruses, enhance physicochemical characteristics, and avoid possible drug resistance that contributes to superior therapies. The best way to produce pharmaceutical drugs that cure SARS-CoV-2 is to find potential molecules from the medicines available for sale [1].

Coronavirus disease 19 (COVID-19) is a remarkably highly contagious and pathogenic infectious disease caused by severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2), which originated in Wuhan, China in December 2019 and spread worldwide. The infectibility of these viruses could only be in the wild before the outbreak of extreme acute respiratory syndrome (SARS) in 2002 and middle-eastern respiratory syndrome (MERS) in 2012 as spotted by the world. While the disease dissipated across the globe throughout the natural environment, the mode of transmission to humans from the wild was insignificant and still unknown. Analysis of the whole genome sequence of the bats, however, was shown to be 96% similar with a severe acute respiratory syndrome-like (SARS-like) bat virus and 79.5% comparable with SARS-CoV, indicating that it is the possible route of transmission to humans [2]. There are four genera of CoVs: Alphacoronavirus, Betacoronavirus (βCoV), Gammacoronavirus, and Deltacoronavirus. Two new βCoVs, extreme acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), have appeared over the past 12 years, and these viruses can cause significant human illnesses. The absence of adequate drug treatment and related elevated morbidity and death rates of these two CoVs, as well as their ability to cause epidemics, illustrate the need for innovative drug development for the prevention of diseases of CoV [3].

### **2. Genomic characterization of SARS-CoV-2**

The size of the genome of the coronavirus ranges from 26 to 32 kb and contains 6 to 11 open reading frames (ORFs) encoding polyproteins with 9680 amino acids [4]. About 80 percent of the SARS-CoV-2 genome has been studied to be similar to the previous human coronavirus (SARS-like bat CoV) while, notable differences in SARS-CoV and SARS-CoV-2 genome have been reported in various studies, such as the lack of 8a protein and perturbations in the number of amino acids in 8b and 3c protein in SARS-CoV-2 [5]. The SARS-CoV2 genome is a polycistronic single-stranded RNA (+ssRNA) with a 5′-cap structure and 3′-poly-A tail (~30 kb), utilized as a template for translating polyproteins (pp1a/pp1ab) into the replication/transcription machinery (RTM) of a double membrane vesicle (**Figure 1**) (6) [6]. RTM subsequently synthesizes a nested set of subgenomic RNAs (sgRNAs) in a discontinuous manner. These subgenomic messenger RNAs (mRNAs) have standard 5′-leader and 3′-terminal sequences between open reading frames (ORFs) on transcription regulatory sequences, where transcription termination and subsequent acquisition of a leader RNA occurs. Such minus-strand sgRNAs serve as models for subgenomic mRNA growth. At least six ORFs comprise the genome and subgenomes of a standard CoVs [7].

For the ORFs from the 5′ end, a region of about 20kb corresponds to the two ORFs; ORF1a and ORF1b encoding 11 and 5 non-structural proteins: nsp1 to nsp11 and nsp12 to 16, respectively. The largest SARS CoV2 ORF1 gene (about two-thirds of the total length of the gene) contains −1 frameshift between ORF1a and ORF1b, resulting in the formation of two conserved polypeptide domains: pp1a and pp1ab. The ribosomal frameshift is involved in the translation of ORF1a directly from the RNA genome, near to the bottom of ORF1, which contains one ORF1ab polypeptide. There are ORFs encoding a few to more than ten structural/non-structural proteins downstream from the ORF1ab [8]. In ORF1ab as well as in other ORFs, CoVs

*Repurposed Therapeutic Strategies towards COVID-19 Potential Targets Based on Genomics… DOI: http://dx.doi.org/10.5772/intechopen.96728*

#### **Figure 1.**

*Genomic organization of SARS-CoV-2. Schematic genomic structure of SARS-CoV-2 based on the SARS-CoV-2 Wuhan-Hu-1. The genome is categorized into two domains: Non-structural proteins and structural and accessory proteins. The S protein contains an S1 and S2 subunit, which are divided by the S cleavage site. Abbreviations: ORF, open reading frame; S, spike; E, envelope; M, membrane; N, nucleocapsid; NTD, N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide; HR1 & 2, heptad repeat 1 and heptad repeat 2, containing the core binding motif in the external subdomain; TA, transmembrane anchor; IT, intracellular tail***.**

often code different non-structural proteins, particularly near the 3′ end, although the specifics of the exact genes in the SARS-CoV-2 genome are still unclear primarily due to overlapping genes encoded in a different coding frame [9]. Two viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are cleaved by the large replicase polyprotein 1a (pp1a) and pp1ab encoded by the 5 terminal open reading frame 1a/b (ORF1a/b) to produce non-structural proteins (NSPs) [10]. The NSPs contain two viral cysteine proteases (nsp3), chymotrypsin like, 3C like, or main protease (nsp5), RNA-dependent RNA polymerase (nsp12), helicase (nsp13) and others that may be involved in SARS-CoV-2 transcription and replication. [4]. In addition, four major structural proteins are coded by ORFs on a third of the genome near the 3′ terminus: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins (**Figure 2**). Different CoVs encode unique structural and accessory proteins, such as HE protein, 3a/b protein, and 4a/b protein, in addition to these four major structural proteins. The sgRNAs of CoVs is translated back from both these structural and accessory proteins [11–13].

#### **Figure 2.**

*The virion structure of SARS-CoV-2. The spike (S), envelope (E), membrane (M) proteins form the envelope of the CoV, and the nucleocapsid (N) proteins form the capsid to pack the genomic RNA.*
