**2.4 Cathepsin L inhibitors**

Cathepsin L is a cysteine protease reside in endosomes and works in acidic pH [41]. It cleaves S1 virus spike glycoprotein and facilitates three actions including virus entry into host cell, virus-host cell endosomal membrane fusion and RNA release. Serine protease (TMPRSS-2) acts on the surface of host cell membrane in neutral pH [42], whereas, cathepsin L mediates its action at host cell membrane as well as inside the endosomes in acidic pH [43]. Therefore, Liu and coworkers, [17] have proposed that the combined use of serine protease and cathepsin-L inhibitors could be effective therapeutics to prevent virus entry and their genome release inside the host cell thereby inhibit the virus replication. In addition, they have also mentioned some cathepsin-L

*Different Therapeutic Strategies to Tackle the Infection Associated with COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.96899*

inhibitors compounds which are found effective against coronavirus infection such as dec-RVKR-CMK, K11777, small molecule 5705213, MDL28170, SSAA09E1, EST, and oxocarbazate. Based on the proposed mechanism, it is reported that the combined use of TMPRSS-2 inhibitors including camostat and nafamostat mesylate along with cathepsin-L inhibitor E64d have shown inhibitory potential against SARS-CoV and SARS-CoV-2 infection in human epithelial cells (**Figure 1**) [44].

### **2.5 Furin inhibitors**

Furin, is a human protease enzyme, present in multiple tissues and highly expressed in lungs [45]. It has been reported that SARS-CoV-2 virus contains furin like cleavage site (FCS) in its spike protein which has made covid-19 virus more pathogenic in nature as compared to other ancestors virus of coronaviridae family [46]. SARS-CoV-2 virus utilizes host furin protease for the cleavage of spike protein and gain entry into the host cell. Moreover, mortalities from SARS-CoV-2 infection have been reported in those patients compromised with cardiac disease, diabetes, obesity and hypertension and likely to be associated with higher circulating furin level [47]. Hence, scientists have drawn attention towards furin inhibitors to provide new therapeutic intervention against covid-19 infection (**Figure 1**).

#### **2.6 Inhibitors of virus structural proteins and enzymes**

Structural proteins and virus encoded enzymes of SARS-CoV-2 may be considered as important drug targets because these are responsible for virus survival and propagation. Researchers and pharmaceuticals companies have focused to develop short interfering RNA (siRNA) based therapeutics to target virus structural proteins and enzymes such as 3CL pro, PLpro and RNA dependant RNA polymerases to combat covid-19 infection [48]. Some previous studies revealed that siRNA therapeutics have already been designed against SARS-CoV and MERS viruses and found effective in outbreaks [49]. In addition, heptad repeat 1 region (HR1) present in the S protein involved in fusion and entry of virus could also be a good target for the development of fusion inhibitors against covid-19 [50]. Xia and co-workers, [51] have developed EK1C4 fusion inhibitors which target SARS-CoV-2 spike protein and found effective in HCoV-OC43 challenged mice. Recently in clinical trials, many chemical peptides, existing drugs and new drug candidates have been recognized through virtual and high throughput screening techniques against SARS-CoV-2 coded enzyme proteases [52]. Based on computational strategy, 6LU7PDB compound has been identified which acts as non-covalent inhibitor of 3CL pro enzyme in SARS-CoV-2 infection [53]. Some 3CL pro enzyme inhibitors antiviral drugs such as lopinavir and ritonavir have been found effective against SARS-CoV-2 virus infection [54]. In addition, some therapeutics are also identified which showed high binding affinity with SARS-CoV PLpro enzyme such as ribavirin, valganciclovir, beta-thymidine and some natural products like platycodin D, baicalin and catechin [55]. Moreover, RNA dependant RNA polymerase (RdRp) inhibitor antiviral drug remdesivir was approved by FDA for emergency treatment for covid-19 patients [56]. However, still its role is controversial for the treatment of covid-19 patients (**Figure 1**).

#### **2.7 Inhibitors of cytokines**

During covid-19 infection, higher amounts of cytokines have secreted from inflammatory cells and serve as potential therapeutic targets for drug development. The major cytokines, IL-6, IL-1, TNF and interferons are generated during cytokine storm which cause the increased vascular permeability, vascular leakage along with dissemination of virus which may lead to fatal pneumonia and acute respiratory distress syndrome [57, 58]. However, many neutralizing strategy against these inflammatory mediators are being used to cope with this cytokine storm in covid-19 pandemic. Chi and co-workers, [59] reported the use of antibodies against IL-6 receptor (tocilizumab and sarilumab) for the treatment of covid-19 infection. Anti-TNF drug etanercept has shown favorable effect in covid-19 patients [60]. Moreover, another targeting approach against cytokine IL-1 is important because it is the major cytokine present in higher amount in alveolar lavage of covid-19 patients and secreted from inflammatory macrophages and monocytes [61]. Cavalli & coworkers, [62] have reported the use of anakirna in high dose and found safe in 72% patients suffered from covid-19 and ARDS with non-invasive ventilation outside the ICU. Furthermore, interferons (IFNs) have immunostimulant and antiviral effects and their use as a treatment along with some antiviral drugs have been found effective against MERS, SARS and IBV viruses (**Figure 1**) [63].
