**5.3 Virus entry and fusion blockers**

S proteins of Coronavirus interact with angiotensin-converting enzyme 2 (ACE2) to initiate entry into the host cell, and hence ACE2 is a critical molecular target for drugs aiming to inhibit cellular access of SARS-CoV-2 [72]. Several drugs have been known to inhibit ACE2, and they are under significant scrutiny for clinical studies.

Chloroquine and Hydroxychloroquine are the drugs from natural sources being employed as the first line of drugs, potential broad-spectrum antiviral drugs. Both are also being used to treat infection by SARS-CoV [73–75]*.* In Simian Vero cells, both chloroquine phosphate and Hydroxychloroquine have shown inhibition of replication of SARS-CoV-2, and in a physiologically-based pharmacokinetic model, 400 mg twice daily was established as the necessary dose [76, 77]. A pilot trial in about ten hospitals from Wuhan, Guangzhou, Jinzhou, Shanghai, Beijing, Chongqing, and Ningbo emphasizes Chloroquine phosphate's superior ability to inhibit pneumonia, reduce viral load, and improving pulmonary findings, and reducing the duration of COVID-19 disease [77]. An open-label non-randomized

clinical trial demonstrated that in 57% of patients, COVID-19 patients who underwent treatment with a daily dose of 600 mg Hydroxychloroquine for six days showed virological clearance. In contrast, in another randomized clinical trial in Wuhan, sixty-two COVID-19 patients showed improvement in 5 days of treatment by a daily dose of 400 mg hydroxychloroquine [39, 78]. This confirmation from the above smaller studies has propelled many prospective studies to investigate Chloroquine and Hydroxychloroquine efficiency in patients of SARS-CoV-2 infection [79, 80].

Umifenovir (Arbidol) is a drug that blocks virus entry inside the host cell by inhibiting endocytosis. It halts viral membrane from fusing into the host cell and subsequent viral entry and has been used in prophylaxis of influenza A and B viruses and inhibits numerous viruses, including Ebola virus, Hepatitis C virus, Lassa virus making it a critical antiviral [81–83]. Arbidol has been tested for its efficiency against COVID-19 conducted in Wuhan, China, where patients receiving 400 mg Umifenovir showed reduced viral load and decreased mortality [84]. A retrospective cohort study among Umifenovir-treated patients showed malicious SARS−COV-2 detection by RT-PCR was, and 69% of patients had improved chest computed tomography scans [85]. These promising results have led to the clinical trial investigation of Umifenovir to be recently initiated [85–88].

Immunotherapy has proven to be effective against infectious diseases such as influenza, SARS, MERS, and Ebola, using monoclonal antibodies (mAbs) to mitigate contagious diseases [89]. Monoclonal antibodies bind to a specific target in the body, enabling it to mimic, block, or cause changes and provide a therapeutic effect for the particular diseases [90]. SARS-CoV-2 and SARS-CoV show many similarities among them, and this suggests the use of SARS antiviral monoclonal antibodies that can identify Receptor Binding Domain (RBD) in subunit S1 in SARS-CoV-2. mAbs can block RBD interaction and its ACE2 receptor, making it anti-spike protein therapy [91, 92]. A cocktail of monoclonal antibodies that can target S-proteins in SARS-CoV and detect different epitopes can potentially destroy viral cells. For example, a cocktail of monoclonal antibodies (MAB)- CR3022 show CR3022, and CR3014 showed neutralization in laboratory setup [92, 93]. Combination of Casirivimab and Imdevimab, popularly known as REGN-COV2 is a monoclonal antibody that can bind to SARS-CoV-2 spike protein and prevent it from entering healthy cells and is under scrutiny for the same. LY3819253- a mAb isolated from a recovered COVID-19 patient, is also under evaluation that has been sponsored by Eli Lilly and Company of Indianapolis, Indiana [94].

#### **5.4 Virus-release blockers**

Oseltamivir, branded as Tamiflu, is Food and Drug Admission (FDA) approved drug that acts as a neuraminidase inhibitor and has since been used popularly in treating influenza A and B [95]. Oseltamivir is being tried as a first-line antiviral drug in symptomatic patients with COVID-19 posts its successful use in SARS-CoV in 2003. A study by Zhang et al. brings light to the fact that that the active site of the Spike (S) 1 Protein of SARS shows a striking similarity to neuraminidase, making use of neuraminidase inhibitors useful to treat SARS-CoV [96]. Clinical trials are currently evaluating Oseltamivir in combination with favipiravir and Chloroquine in treating SARS-CoV-2 infection [97].

#### **5.5 Non-virus-targeting treatments**

Tocilizumab is a humanized mAb employed in Rheumatoid Arthritis treatment, and numerous studies have included tocilizumab for consideration as

#### *Coronavirus Disease 2019 (COVID-19): Origin, Impact, and Drug Development DOI: http://dx.doi.org/10.5772/intechopen.98358*

anti-SARS-CoV-2 therapy. A larger multicentred clinical trial of tocilizumab has been launched in China and had about 500 patients treated already enrolled [98, 99]. Anakinra is an FDA-approved modified human IL-1 receptor antagonist (IL-1RA) for RA treatment, which blocks innate immune response associated with cytokine storm resultant inflammation [100, 101].

Dexamethasone is a glucocorticoid that curbs lung injury resultant from inflammation, respiratory failure, and death in ARDS by decreasing ventilator days and mortality. World Health Organization has put Dexamethasone on the list of essential medicines. National Institutes of Health has recommended glucocorticoids in patients hospitalized with Covid-19 in the United States [102]. Randomized Evaluation of COVID-19 Therapy (RECOVERY Trial) - a large human study was initiated in the United Kingdom by Oxford University in March 2020 to test the utility of several previously known drugs against the COVID-19 trial. The initial report announced that Dexamethasone at a dose of 6 mg once daily for up to 10 days could bring down mortality significantly in critically ill COVID-19 patients validating the use of Dexamethasone for COVID-19 patients [103]. In another recent trial, dexamethasone therapy given to patients showed 15% lower mortality in ARDS patients [104].

CD24Fc, also known as Cluster of differentiation 24, is a recombinant fusion protein and a biological immunomodulator comprising the Fc region of human Immunoglobin G1 (IgG1) attached to the nonpolymorphic areas of CD24, making it an innate checkpoint against the inflammatory responses against tissue injuries associated with cytokine storm. The protection and biological activity of CD24Fc in suppressing the expression of multiple inflammatory cytokines have been demonstrated in preclinical and clinical studies carried out. A Phase II clinical trial in patients with leukemia indicates that three doses of CD24Fc effectively eliminated the appearance of extreme acute Graft vs. Host Diseases (GVHD) due to overreacting immune system and recipient target attacking transplanted T cells. CD24Fc may therefore be investigated as a prime candidate for non-antiviral COVID-19 therapy intervention for the control of cytokine storms in affected cells [105].

Dapagliflozin (Farxiga), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, has currently been assessed under "Dapagliflozin in Respiratory Failure in Patients with COVID-19" or DARE-19 in a phase-3 randomized trial designed to evaluate its efficacy as a treatment option for COVID-19 at risk of developing comorbidity such as organ failure [106]. SGLT-2 inhibitors play a role in instigating the reninangiotensin-aldosterone pathway through the expression of angiotensin-converting enzyme type-2 (ACE2). Renin-angiotensin-aldosterone system (RAAS) pathway is essential in the pathophysiology of SARS-CoV-2. Organ-protective effects are provided by SGLT-2 inhibitors complementary to its glycaemic benefits and hence may afford additional vital organ protection to the patients [107, 108]. Patients in DARE-19 are to be treated with a daily dose of 10 mg Dapagliflozin once a day.

### **6. Future prospective**

The evolution of Zoonotic Chinese Coronavirus SARS-CoV-2 needs to be better monitored through implementing better surveillance and precautionary steps. Due to this COVID-19 pandemic, scientists worldwide were encouraged to search for novel therapeutic options, including vaccines, drugs, and diagnostics. However, until now, there is no effective treatment approved and recommended for COVID-19 globally. Utilization of such computer-aided-drug design (CADD) and bioinformatics tools such as Immune Epitope Database (IEDB) software to predict a computational vaccine and target drug compounds for COVID-19 is

also encouraging [109]. In this way, drug repurposing emerged as a promising therapeutic approach in a time-saving and cost-effective manner. There are many drugs repurposed in the case of COVID-19 treatment. Drugs like Remdesivir, Dexamethasone, and a combination of Lopinavir-Ritonavir, reported positive outcomes to treat COVID-19.

Similarly, there are currently more than 100 vaccine candidates under development for the COVID-19, and it will likely be ready by early/late 2021. 38 Vaccines are in the first stage for the testing safety and dosage, 17 Vaccines are in their second phase and expanded safety trials, 12 Vaccines are in the third phase comes in large-scale efficacy tests, and 6 Vaccines approved for first or limited use. None of the vaccines are approved for full use. The safety issue is concerning and the most significant challenge when tested in diverse populations, especially in countries like India and China. Large-scale production, storage, and distribution of vaccines are also another challenge. However, further investigations and experiments are needed to discover an effective treatment option.
