**4.3 Structural protein inhibitors**

For the entry of coronavirus into a host cell, transmembrane Spike (S) glycoprotein is essential. Fusion of the membrane and activation of the virus entry require cleavage at the S1–S2 junction and because of their vital role in the interaction between the virus and the cell receptor, spike protein can be an important potential target for antiviral agents [76]. The receptors that mediate the fusion of the S protein of SARS-CoV2 into the host cell are angiotensin converting enzyme-2 (ACE-2) and type 2 transmembrane protease serine (TMPRSS2). Cleavage via TMPRSS2 the fusion of the S protein to the ACE-2 receptor is achieved and thus are the potential drug targets in the SARS-CoV-2 therapeutics [51]. Umifenovir (Arbidol) [NCT04350684], an antiviral drug has been found to block and effectively prevent the trimerization and cell adherence and entry of SARS-CoV-2 spike glycoprotein interacting with the key residues in the target domain indicating as the potential target [77]. Griffithsin, a lectin protein has demonstrated antiviral properties and can potently inhibit viral entry and prevent binding to the S glycoprotein both in vitro and in vivo SARS-CoV infection with limited cytotoxic effects. Previous studies have shown griffithsin to inhibit MERS-CoV infectivity in *in vitro* assays without any noticeable cytotoxicity [78]. Camostat mesylate [NCT04608266] can feasible therapeutic choice for COVID-19 as it decreases the unregulated release of cytokine observed in extreme COVID-19, regardless of its antiviral function, because TMPRSS2 expression is necessary for vigorous secretion of cytokine when mice are exposed to polyIC [79]. Bromhexine hydrochloride [NCT04355026] (BRH) inhibits the viral entry of transmembrane protease serine 2 (TMPRSS2) and is potentially known to be protective against SARS-CoV-2 [80]. Eriodictyol, a *Herba santa* flavanone, is a popular herbal medicine used to cure asthma and colds. In silico studies predicts, eriodictyol binds to almost all targeted proteins with good energy and has shown its relevance for COVID 19 therapy [81].

SARS-CoV-2 nucleocapsid (N) protein is a multifunctional protein that plays a key role in the assembly of the virus and its transcription of the RNA. During

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

#### **Figure 11.**

*Repurposed structural and accessory protein inhibitors for COVID-19 treatment.*

the packing of the RNA genome, the N protein is critical in the creation of helical ribonucleoproteins, controlling viral RNA synthesis during replication and transcription. Infected host cells and their cellular functions are also regulated by the N protein [82]. Previous studies identified a special ribonucleotide-binding pocket composed of strongly conserved residues in the NTD by solving the complex structure of CoV NP-NTD bound with ribonucleotide monophosphate. Compounds that bind to this RNA-binding pocket may inhibit normal NP function and may be used to regulate CoV diseases. 6-chloro-7-(2-morpholin-4-yl-ethylamino) quinoxaline-5,8-dione (H3) (**Figure 11**) revealed inhibitory activity on the RNA-binding of NP [83]. Mefuparib hydrochloride, CVL218, a Poly [ADP-ribose] polymerase 1 (PARP1) inhibitor have shown to exhibit effective inhibitory activity against SARS-CoV-2 replication without apparent cytopathic effect in *in-vitro* and *in-silico* studies [84]. Zidovudine triphosphate, an anti-HIV drug, acts as a potential inhibitor of the N-terminal domain of SARS-CoV2 N-protein based on docking and simulation research, and can be considered to repurpose for therapeutic options to fight COVID-19 [85]. Out of 13 molecules analyzed for the molecular simulation study on SARS-CoV-2 nucleocapsid protein, 3 (Varespladib, MK-5108, Stepronin) have been found to be show inhibitory activity on SARS-CoV-2 N protein with high docking score [86].

#### **5. Vaccines approved for emergency use authorization (EUA)**

Various vaccines across the globe are in the progress of development against COVID-19, while the efficacy, productive and stability of most of them is still unclear. The latest report from the World Health Organization states about 69


**Table 1.**

*Vaccines against COVID-19 approved for emergency use authorization.*

vaccine candidates in the progress of clinical trial and about 181 candidates in pre-clinical development [87]. About 7% of vaccinations in the state of preclinical trials performed are based on practice. Hereby, we list the current status of several vaccines across the globe approved by Food and Drug Administration (FDA), European Medicine Agency (EMA), World Health Organization (WHO), Indian Council of Medical Research (ICMR) and other countries medical advisory boards under progress of development for the emergency use authorization (EUA) in order to curb the pandemic (**Table 1**).
