Drug Development Strategies and Immunological Aspects of SARS-CoV-2

1.1. A Brief History and Reservoir of the Virus

In December 2019, researchers in the Chinese city of Wuhan identified this year's novel coronavirus, which was dubbed the “2019 novel coronavirus” (2019-nCoV) [10, 11]. Additionally, the virus has been linked to pneumonia and, in some instances, an increased risk of progressive respiratory failure resulting from alveolar damage. Fever, dry cough, dyspnea, and headaches have been reported as the most common symptoms [12]. The virus was genetically analyzed and genetically identical to the SARS-CoV strain responsible for the 2002 and 2003 outbreaks. As a result, the virus was renamed SARS-CoV-2 in February 2020 to emphasize this connection. Acute respiratory distress syndrome (ARDS) can be caused by several viruses, including SARS-CoV, MERS-CoV, and other CoV infections and severe COVID-19 infection ARDS [13]. Proinflammatory cytokines are produced at dramatically increased levels in patients with ARDS [11, 14-16]. An excessive release of cytokines results, which is considered a contributing cause in multiorgan failure and greater death rates in the general population. In extreme situations, the disease can have pathophysiological consequences for the heart, kidneys, liver, and central nervous system, depending on various circumstances, including past diseases and immune system responses [17, 18]. Acute illness can have various other adverse effects on the body and its pathophysiological effects on the lungs. Arrhythmias, an increased risk of myocardial infarction, liver dysfunction, and kidney failure are only a few potential side effects, including neurologic symptoms such as ataxia, seizures, neuralgia, acute cerebrovascular illness, and encephalopathy [2, 6]. The virus that causes SARS-CoV-2 can infect tissues other than the lungs, and it is expected that the disease will worsen in these tissues if it does [19].

Based on genomic and phylogenetic analyses [4, 6], the coronaviruses SARS CoV, MERS CoV, and SARS CoV-2 have been identified as zoonotic infections caused by coronaviruses that can spread to humans either directly or indirectly via an intermediate host. It is believed that bat coronaviruses, most likely transmitted from bats to humans through direct contact with bats, are the source of a wide range of diseases. Since there is a lack of available data on viral sequences in these animals, determining the likely zoonotic potential of newly identified viruses is extremely difficult to predict. According to a few studies, the SARS-CoV-2 virus spreads more rapidly than the SARS or MERS viruses [20]. All three viruses are widely transmitted in nosocomial settings and exhibit symptoms that are similar to one another. Asymptomatic patients must be closely examined frequently to guarantee that viral shedding does not occur before the onset of clinical signs and symptoms [21, 22]. Researchers have discovered that the presence or absence of signs and symptoms in the transmission of infectious viruses considerably enhances the pandemic potential of an infectious virus [23]. According to WHO, it was declared a pandemic by the World Health Organization on March 11, 2020, due to the rapid and exponential increase in the number of illnesses and fatalities associated with COVID-19 over such a short period of data. Over 10 million disease cases will have been documented worldwide by June 2020, with more than 500,000 people dying due to sickness by that time [24], and now there have been 251,788,329 confirmed cases of COVID-19, including 5,077,907 deaths, reported to WHO. As of November 10, 2021, a total of 7,160,396,495 vaccine doses have been administered [25]. The treatment options for COVID-19 are limited to FDA-approved antiviral or EUA drugs. At the same time, simultaneously, many SARS-CoV-2 vaccines are now being studied and assessed in clinical studies, and others are already approved. In a clinical phase 3 trial using COVID-19 [26], researchers discovered that Remdesivir, an experimental drug originally designed as an RNA-dependent RNA polymerase (RdRP) inhibitor against the Ebola virus (EBOV), proved effective [27]. It was initially intended as an RNA-dependent antiviral treatment when Remdesivir was developed as an investigational medicine. According to researchers from the University of California, people admitted to the hospital with COVID-19 and administered remdesivir had a 31 percent shorter recovery time than those who were not given remdesivir during their hospitalization (from 15 to 11 days) [28]. The Food and Drug Administration (FDA) of the United States declared on May 1, 2020, that Remdesivir had been approved for the treatment of COVID-19, even though formal approval had not yet been issued.

1.2. COVID-19 Infection and Treatment Strategies

A simple cleaning with soap or detergent, on the other hand, would immediately eradicate the COVID-19-causing SARS-CoV-2 virus [16]. The virus may live in aerosols for several hours and on surfaces such as stainless steel, plastic, and cardboard for several days [16]. If the virus can propagate during the time of asymptomatic incubation (expected to occur in 50–60 percent of cases), it can be disseminated for up to two weeks after the beginning of symptoms [29]. According to the Centers for Disease Control and Prevention (CDC), three other people get infected for every sick individual. Incubation time in a laboratory setting is usually 5–6 days (with a range of 1–14 days). Clinical indicators can range from asymptomatic infection to mild disease to severe or fatal sickness; thus, knowing the whole range of possibilities is crucial [29, 30]. When comparing severe to moderate cases, some estimates suggest that the viral load in individuals with severe symptoms could be up to 60 times higher than in people with mild symptoms. According to medical authorities, pneumonitis and possibly hyper inflammation linked to cytokine storm syndrome are the leading causes of death [12, 18, 21, 31].

Fever and chills were the most prevalent COVID-19 symptoms in Europe (49 percent), followed by dry or productive cough (24 percent), sore throat (12 percent), overall weakness (8 percent), discomfort (7 percent), and then rhinorrhoea (4 percent) and diarrhea (4 percent) (2 percent). Myopathy of the heart, thrombosis of the blood vessels in the brain, and encephalitis are all possible complications [30]. Immunosuppression and other risk factors, including aging and a minority ethnic background, are linked to an increased risk of severe disease and mortality [12, 16]. COPD, cardiovascular disease, hypertension, and other comorbidities, including diabetes, are also strong predictors of critical care admission [12, 30].

The latest studies reveal that mild SARS-CoV-2 infection could be associated with physiological immuno-thrombosis and controlled by body homeostatic mechanism, while in severe cases, uncontrolled physiological immuno-thrombosis may be controlled, extended and developed into pathological immuno-thrombosis [32, 33].

The virus's affinity for ACE2, expressed by epithelial cells in the lungs, colon, kidney, and vasculature, among other sites, is most likely to blame for these risk factors [31]. ACE2 expression is higher among older people, smokers, and individuals with diabetes or hypertension, many of whom use ACE inhibitors, GLT-1 inhibitors, or ibuprofen, compared to the general population [34]. According to two recent Italian and American studies [35], taking an ACE inhibitor or angiotensin II-receptor blocker (or any other single antihypertensive medicine) is not linked to a higher risk of COVID-19 infection, severe symptoms, or death. However, as a result of the evidence, an increased risk of cardiovascular disease has been established, implying that the correlation is causal.

There is little evidence linking NSAIDs/ibuprofen to COVID-19 susceptibility or worsening of symptoms, according to the most recent advice from the Commission for Human Medicines [36]. Patients can self-medicate for COVID-19 symptoms with paracetamol or ibuprofen if they are regularly taken in prescribed amounts. However, additional difficulties may occur, and NICE's brief evidence summary (ES23) [37] summarises all information that is currently available on the subject.

In addition to its antihelminthic effects, niclosamide (NCL) also has pleiotropic anti-inflammatory and antiviral qualities, making it a frequently used medicine in treating a broad spectrum of illnesses. It is thought that NCL affects human biological processes by controlling uncoupling, oxidative phosphorylation, and several signaling pathways. The broad-spectrum antiviral activity of NCL suggests that it may be a potential therapy option for the present pandemic SARS-CoV-2 infection. It may also effectively reduce the severity of COVID-19 infection in some cases [38].

According to a recent study, the SARS-CoV-2 virus uses the enzyme dipeptidyl peptidase 4 (DPP4) as an entrance site into various organs that carry these receptors [39]. In addition to its anti-inflammatory and antioxidant properties, DPP4 inhibitors (also known as gliptins, such as sitagliptin) have been shown to assist patients with type 2 diabetes. These effects have been shown to help reduce inflammation and oxidative stress in diabetic COVID-19 patients. Furthermore, increased levels of dipeptidyl peptidase 4 were discovered in patients with COVID-19 who did not have diabetes, which has been identified as a potential positive effect of sitagliptin in the therapy and management of this condition [40].

Favipiravir is effective against viruses that cause hemorrhagic fever and encephalitis, both life-threatening diseases. Rotaviruses, filoviruses, bunyaviruses, flaviviruses, and filoviruses are examples of viruses that fall within this category. Because many viruses do not have vaccines or antiviral drugs approved by the FDA, discovering effective antiviral therapeutics with a broad spectrum of activity is essential. Unlike other known influenza antivirals, which hinder virus movement both within and outside cells, favipiravir works by impeding virus movement within cells. In addition, prodrugs are modified via phosphorylation and ribosylation. Finally, a conversion step is performed to transform the medicine into its active form, favipiravir-RTP, which is effective against HIV. In its active form, Favipiravir-RTP inhibits the transcription and replication of the RNA-dependent RNA polymerase (RDRP (RdRp). This interferes with virus genome transcription and replication, resulting in a decrease in virus activity. Given favipiravir's novel mechanism of action, particularly in viral infections, it is critical to concentrate on the drug's efficacy, dosing regimen, and interactions with other drugs [41-43] (Table 1).

Within a year of their introduction, several vaccines are available for distribution. According to the WHO, nine vaccines have been approved and have extensive use from at least one regulatory authority (Pfizer–BioNTech, Oxford–AstraZeneca, Sinopharm BIBP, Moderna, Janssen, CoronaVac, Covaxin, Novavax, and Medicago), and five more are under evaluation (Sputnik V, Sinopharm WIBP, Convidecia, Sanofi–GSK and SCB-2019) [60].

Levamisole (LVM) is an antihelminthic medication that increases the type 1 immune response. These findings imply that LVM could help prevent and treat SARS-CoV-2 infections. Latest studies demonstrated that LVM might be used to treat SARS-CoV-2 and COVID-19 infections in humans [44]. LVM has been linked to a reduction in SARS-CoV-2 replication by blocking a papain-like protease, according to several investigations (PL-pro). This is because LVM activates glucocorticoid receptors in the kidney (AKI). LVM has a strong immune system stimulant impact, affecting cellular and humoral immune responses. Early in COVID-19, this influence is good, but later on, it is unfavorable. SARS-CoV-2 clearance and tissue healing are boosted by early immune activation, whereas late activation increases the risk of cytokine storm amplification. Finally, LVM therapy had a mixed effect on COVID-19, initially favorable but eventually deleterious. Clinical trials and prospective research are needed to prove LVM's efficacy and timeliness in treating COVID-19 [44].

Without question, the most effective technique for COVID-19 disease prevention is a good immunization campaign. However, there are a few key aspects to consider. First, both SARS-CoV and MERS-CoV are under ten years old, and neither has been around for more than twenty years. Second, the FDA has yet to approve vaccines for these diseases, although several promising prophylactic techniques are in the works. Malaria, HIV/AIDS, Ebola, and Zika virus are just a handful of infectious diseases for which no effective vaccinations are available (Zikavirus). Third, vaccine development can take ten to fifteen years and is quite expensive [22, 61, 62].

Furthermore, fast changes in viral RNA may render these vaccines ineffective. RNA viruses change rapidly [63, 64]; however, the S protein amino acid residue sequences of emerging SARS-CoV-2 variants from different countries do not appear to differ considerably [61]. According to preliminary evidence, vaccine-induced antibodies increase the prevalence and severity of disease during subsequent host-pathogen interactions [62]. Antibodies that aid the virus rather than the host are created in a process known as antibody-dependent enhancement (ADE). This strategy allows the virus to benefit more than the host by speeding up viral entry and reproduction in the target cell [63]. Despite identifying ADE in dengue, HIV, respiratory syncytial virus, and influenza virus infections [62], there have been no confirmed instances of SARS or EBOV.