Introduction

December 2019 has been documented as a historic month for the emergence of the coronavirus disease also called viral pneumonia in Wuhan, China. This outbreak has propounded to approx. 220 countries, possessing more than 180,906,466 confirmed cases with 3,919,082 confirmed deaths and recovered cases 165,531,010 all over the world until the 25th of June 2021.

The virus was primarily cautiously named 2019 novel coronavirus (2019-nCoV). Consequently, the International Committee of Taxonomy of Viruses coined the name SARS-CoV-2, and so the disease was named COVID-19(Zhou et al. 2020; Chen et al. 2020). This virus has been classified in genus, subgenus, and family: β-coronavirus, Sarbecovirus, and Coronaviridae respectively (Fig. 1) (Zhang et al. 2020a; Pottoo et al. 2021).

Fig. 1
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Structure of SARS-CoV-2 virus

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SARS-CoV-2, extremely contagious and lethal, became an immense global health issue. As per the gene sequence analysis, SARS-CoV-2 is pertinent with two SARS-like coronaviruses observed in bats (approx.88% resemblance) that possess rapid spreading characteristics all through the world. There are seven strains of coronavirus detected and identified which infect humans (HCoV), four of which are HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43 that are common, seasonal, and liable to cause mild respiratory symptoms, whereas another two are zoonotic and virulent called MERS-CoV and SARS-CoV-1 and this SARS-CoV-2 possesses genetic similarity with SARS-CoV-1, both belonging to Sarbecovirus subgenus and β-coronavirus genus (Chen et al. 2020). Further study revealed that virus possesses envelope, +ve sense, single-strand of RNA linked with 30-kb genome (Arabi et al. 2020). It possesses proofreading machinery in order to reduce the mistakes during replication, therefore the mutations.

Research on SARS-CoV-2 revealed that it corresponds to Beta-coronavirus that possesses a characteristic genome structure as shown in Fig. 1. This virus is the biggest known RNA virus that has a specialty in possessing a replication-transcription system (RTS). This also possesses 3′-5′ exo-ribonuclease (some RNA-transforming enzymes with approx. 148 proteins). The mechanism of infection in a human cell has been illustrated in Fig. 2 (Cevik et al. 2020).

Fig. 2
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Mode of infection of SARS-CoV-2 in human cell

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Decoding of genome results into structural (four proteins, i.e., spike, membrane, envelope, and nucleocapsid) as well non-structural proteins (for replicase transcriptase proteins). It binds to ACE2 receptors through spike protein for cell attachment and entry. The disease shows flu-like symptoms such as fever, cough, loss of taste, diarrhea, pneumonia, renal, asthenia, cardiac symptoms, and skin rashes. Happy hypoxia is also observed in COVID-19-positive cases which is also responsible for the causalities. In some situations, the patient also feels acute traumatic stress disorder, depression, and some psychological disorders, and few cases commit suicide also due to it (Markham and Keam 2018). The effect of SARS Cov-2 on various vital organs is shown in Fig. 3.

Fig. 3
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Effect of SARS COV-2 on vital organs

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Coronavirus strains

The coronavirus term implies a huge virus’s family known since a long time ago. Before this pandemic, many coronaviruses are known to infect humans and cause mild respiratory illnesses such as cough and colds. This novel COVID-19 virus is not new to us but it is very rare that a virus jumps from animals/plants to humans and causes disease. This happens with the COVID-19 virus; therefore, it infects humans rapidly, due to its extreme contagious nature (Jena 2021; Jha et al. 2021;Jin et al. 2020;Shahab et al. 2021, Huang et al. 2020). Variants known to date are compiled in Table 1.

Table 1 Different variants of COVID-19
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Mutations

It is well known that viruses are the link between living and non-living organisms as they do not contain any cells. Therefore, there are more chances of mutations in viruses during human infection as well as disease progressions as the simplest structure. Most of the mutations are harmful to the organisms but few may be beneficial too. As a result of mutations, these viruses may appear in a little bit different form and can cause the disease in an extreme contagious manner as shown in the case of the COVID-19 virus.

D614G was found to be the first variant that has been observed near late January or early February 2019 and replaced the original strain somewhere in June 2020 which became dominant and spread throughout the world. The enhanced infectivity and transmission have been observed without a change in the severity of the disease.

Cluster 5, another mutant, has been observed somewhere between August and September 2020 through Danish personnel infected by framed mink which later jumped to humans. As the name suggests, Cluster 5 is an aggregate of strains, observed in 12 persons until now, not found to spread extensively. SARS-CoV-2 VOC 202012/01 (mutant of interest) has been reported by UK personnel to the WHO (December 14, 2020). This mutant possesses 23 nucleotide changes found to be not related phylogenetically to the SARS-CoV-2 virus, the main cause of coronavirus disease at that time. Due to the above substitutions, this strain was found to possess enhanced transmissibility without any change in disease severity (Ruan et al. 2020). The variants that are known and the different mutants along with the site of mutations are summarized in Table 2.

Table 2 Different mutant along with site of SARS-COVID-2
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Triple COVID-19 mutation

Triple mutation in COVID-19 has also been observed in few parts of Delhi, West Bengal, and Maharashtra. Mutations at sites 452 and 484 have been reported individually; for example, in California, variants B.1.427 and B.1.429 have the L452R mutation. E484K has been seen in the variants reported from the UK, South Africa, and Brazil. Mutations at site P681 have also been seen in some lineages before as well as the mutation E484Q. The combination of all the three mutations reported here, L452R, E484Q, and P681R, suggests the virus emerging similar traits autonomously, continually adapting to its human hosts (Perrella et al. 2020;  Del Rio et al. 2020).

Pathogenesis of disease

When a virus enters in body through the nose or mouth, it stays near the paranasal cavity and tries to make colonies, which results in headache and loss of smell and taste at the very first level. After 24–36 h, it invades the respiratory and gastrointestinal system and causes abdominal pain and loss of motion. The body defense system activates, and macrophages accumulate at the site and try to engulf the virus and send the messages in a form of IL-1, IL-6, and TNF to other body cells as well as neutrophils to be active against infection.

By the examining IL-6 level, we can make an idea regarding the body’s preparation against the virus. As the disease progresses, further neutrophils accumulate and try to kill the virus, but body cells will also be affected. At 5–6 days of the disease, chances of cytokine storm occur due to over responsiveness of the body. The virus attacks on type 2 pneumocytes, which secrets some surfactants and helps in lung expansion during respiration. Another target for the virus is the liver and kidney. Macrophage activates the liver to produce a c-reactive protein which gives signals to other parts of the body to be overreactive against infection (Jain 2020).

These signals can also act on the liver to produce and release fibrinogen which when reacts with platelets forming unnecessary clots in the body which floats in the blood and can block any artery/vein that may result in pulmonary embolism, heart attack, and stroke. These blood clots can be examined by testing the level of d-driver. When an infection invades the heart cells, it releases HSCRP which causes damage to the cardiac muscle cells. Cytokines can activate the thermo regulators in the hypothalamus and result in fever. The liver function and cell damage can be checked by examining SGOT, SGPT, blood level. Cell damage can be checked through LDH level and a patient’s life can be saved by taking therapy on time (Favalli et al. 2020).

Once SARS-CoV-2 enters the alveolus, it begins to infect type II alveolar cells and replicate. The infected type II alveolar cells release pro-inflammatory cytokines, which signal the immune system to respond. Patients may experience mild symptoms, such as cough, fever, and body aches. Macrophages release IL-1, IL-6, and TNF-I. IL-6, causing vasodilation and allowing more immune cells to travel to the alveolus. It also increases capillary permeability, causing plasma to leak into the interstitial space and the alveolus. Neutrophils release reactive oxygen species and proteinases, which destroy infected cells. These dead cells combine with the plasma to form a protein-rich fluid that accumulates within the alveolus, causing shortness of breath and pneumonia. Accumulation of fluid and dilution of surfactant lining of the alveolus cause alveolar collapse, which decreases gas exchange and can lead to hypoxemia and acute respiratory distress syndrome. If the immune system goes into overdrive, inflammation can spread throughout the circulatory system, leading to systemic inflammatory response syndrome, also known as a cytokine storm. This systemic inflammation can cause septic shock, where blood pressure drops dangerously low and organs can no longer be perfused, leading to multi-organ failure and death.

COVID-19-related comorbidities

As explained in the preceding sections, the SARS-Cov-2 virus has undergone numerous changes, resulting in more dangerous variants. In type 2 asthmatic individuals, COVID-19 infection becomes more severe. They also outline the treatment options and medications that can be utilized to address mild, moderate, and severe COVID-19 symptoms in asthmatic patients, preventing aggravation. The progressive results were highly contradictory, as severe cases of COVID-19 showed an increase in the levels of numerous cytokines that might exacerbate bronchial tract inflammation, exacerbating asthma attacks. Contrary to popular belief, certain data show that COVID-19 severity is reduced in type 2 asthmatic patients with elevated T-cells, since most COVID-19 positive individuals have a significant drop in T-cells. This helps to restore the balance of immunological responses, slowing the advancement of the disease (Ghosh et al. 2021).

Obesity stimulates the development of gene-induced hypoxia and adipogenesis in obese mice. Obesity increases the likelihood of developing immune-mediated and certain inflammatory-mediated illnesses, such as atherosclerosis and psoriasis, by dampening the immunological response to infectious pathogens, resulting in weakened post-infection effects. Furthermore, the obese host produces a unique milieu for disease development, characterized by low-grade inflammation that persists. To protect our bodies and reduce the danger of infectious illnesses, including COVID-19, it is recommended to maintain good eating habits by increasing the intake of diverse plant-based and low-fat meals (Behl et al. 2020).

The virus appears to enter the CNS mainly via the angiotensin-converting enzyme-2 (ACE-2) receptor and nasal route through the olfactory bulb and cribriform plate and propagates through trans-synaptic signaling, and moves retrogradely into the CNS along the nerve fiber, according to evidence. Parkinsonism, Alzheimer’s disease, meningitis, encephalopathy, anosmia, hyposmia, anxiety, sadness, psychiatric symptoms, seizures, stroke, and other problems have been linked to viral invasion of the CNS. As a consequence, even after the individual has cured from COVID-19, the COVID-19 CNS components should be checked on a regular basis to prevent long-term CNS issues (Nagu et al. 2020).

Diagnosis

Recently, two types of tests have been performed for the diagnosis:

  1. a.

    Molecular tests

  2. b.

    Antigen tests.

Molecular test detects viral genome whereas antigen tests target characteristic viral proteins.

Antibody test targets the antibodies that have been produced in patient’s blood with response to viral infection but it can be detected in post-COVID-19 patients also (Shahab et al. 2021; Ojha et al. 2021; Shoaib et al. 2021). Diagnostic tests are compiled in Table 3 and Fig. 4.

Table 3 Diagnostic tests for SARCOV-2
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Fig. 4
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Diagnostic tests employed for SARS COV-2

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Drugs used in the management of SARS COV-2 infection

The repurposed drugs used in the management of SARS COV-2 infections (Pawelczyk and Zaprutko 2020; Parasher 2021; Saxena 2020; Gil et al. 2020) are listed and compiled in Table 4. Different drugs along with the mechanism of action in the management of SARS COV-2 are shown in Fig. 5.

Table 4 Repurposed drugs used in the management of SARS COV-2
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Fig. 5
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MOA of drugs for management of SARS COV-2 disease

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Mechanism of action of drugs for the treatment of SARS-COV-2

Chloroquine/hydroxychloroquine

The mechanism of chloroquine and hydroxyl-chloroquine drugs involves the conversion of chloroquine to hydroxychloroquine which in turn inhibits several enzymes. Due to enzyme inhibition, viral entry is inhibited due to these weak bases because of pH dependency. The drug also inhibits glycosyl-transferases and post-translation modifications and also inhibits viral families. The mechanism of action is depicted in Fig.6 (Schrezenmeier and Dörne 2020).

Fig. 6
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Mechanism of chloroquine/hydroxychloroquine

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Favipiravir

Favipiravir is an approved drug employed for severe influenza virus infection in China. It is available in an inactive form and gets converted into an active form by the action of enzymes into favipiravir ribo-furanosyl monophosphate (RMP) which further converts into the active form (favipiravir ribo-furanosyl triphosphate) which in turn can block the replication of several RNA viruses currently in clinical trials in COVID-19 management. The mechanism of action has been presented in Fig. 7 (Sood et al. 2021).

Fig. 7
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Mechanism of Favipiravir in the treatment of SARS COV-2

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Remdesivir

It is a broad-spectrum antiviral drug; adenosine analog that can determine pre-mature termination of viral RNA. It has been tested for Ebola virus infection and might be useful in the treatment of other RNA virus infections. It has been shown that the action against SARS COV-2 infection also, still, studies are going on and showed in Fig. 8 (Beigel et al. 2019; Wang et al. 2020a).

Fig. 8
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Mechanism of action of remdesivir in the treatment of SARS COV-2

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Monoclonal antibodies

Monoclonal antibodies can be produced by immunizing the rats with antigens but sometimes failed to secrete antibodies. This can be further modified by mixing the myeloma cells with plasma cells from the spleen. Cell fusion results in hybridomas cells, which are transferred to hat medium and incubated. Hybridomas cells are further selected which produced antibodies known as monoclonal antibodies. These antibodies are found to be effective against COVID-19 and came in light when given to the ex-US president Donald Trump. The monoclonal antibody cocktail is a combination of two or more monoclonal antibodies which is administered to the patient as a single dose. These are found to exhibit activity by acting on the spike protein of the COVID-19 and do not allow it to enter into the human cell. For the treatment of mild to moderate covid infection, the combination of Bamlanivimab (700mg) and the mixture of Casirivimab and Imdevimab (2400mg) appeared to accelerate decline SARS-COV-2 level compared to placebo. Casirivimab and Imdevimab are mainly human immunoglobulin G-1 (IgG1). Figure 9 describes a method of production of monoclonal antibodies (Richardson et al. 2020; Ceribelli et al. 2020; Marovich et al. 2020; Zost et al. 2020; Goyal et al. 2021;Yang et al. 2020; Clinical Trial Arena 2020; Phan et al. 2021).

Fig. 9
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Production of monoclonal antibodies.

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Recently, Zydus claimed regarding the repurposing of “Virafin” (pegylated interferon alpha-2b) in COVID-19 treatment which was earlier used in the treatment of the hepatitis C virus. Recently, Virafin has been given limited emergency approval from DCGI, India (Science The Wire 2021).

One more drug named “2-DG” has been developed by DRDO along with Dr. Reddy’s Lab. Hyderabad has been granted emergency approval from DCGI, India as an adjunct therapy to overcome oxygen demand. This drug has been developed in the treatment of cancer as it possesses promising cytotoxic potential (Economic times. Indiatimes 2021).

Currently, Canadian company Sanotize developed nitric oxide–based nasal spray, claimed to kill COVID-19 load inside the nose up to 99.99 %. Now, the company has filed for getting emergency approval in the UK and started its production in Israel (India today 2021).

Approved and phase 3 trial vaccines

Vaccines are the hope for controlling this pandemic caused by the COVID-19 virus. Few vaccines have been approved by regulatory authorization whereas some of them are in the process. It should be very clear that no vaccine is 100% effective until now; still results will prove the efficacy and safety of the vaccines. Each and every person must follow the guidelines and hygienic conditions. Scientists all over the world are working at war level for the production of vaccines; until now, 79 vaccines are still in process and among them, 11 vaccines have been approved by regulatory authorities whereas 20 vaccines are still in phase III clinical trials (Li and De Clercq 2020; Li et al, 2020a; Zoomer 2021; Graham, 2020) Vaccines that have been approved by regulatory authorities until now are shown in Table 5. The list of approved vaccines in phase trial 3 is compiled in Table 6.

Table 5 List of approved vaccines for COVID-19
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Table 6 List of vaccines in phase 3 clinical trial
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Nano-medicines in SARS Cov-2 infection

Nano-technology possesses enormous potential in targeted drug delivery at the target site with minimum side effects, especially in the anticancer domain. This technology has been extensively utilized in the development of vaccines against the COVID-19 virus.

Viruses can be categorized as nanoparticles, which work at similar measures as other nanomaterials. There has been a lot of research performed as well as ongoing to mimic the nanoparticle-like virus behavior for designing the target drug release as well as gene delivery regimens (Singh et al. 2017). Therefore, nanotechnology may offer great value in the present ongoing pandemic via various ways such as viral neutralization and detection, vaccine developments, and providing effective treatment (Florindo et al. 2020).

Nanoparticles possess similarity to coronavirus, excluding viral genome if nanoparticles enter the host cells renovate immunity against this type of infection. Due to similar size nanoparticles may bind to the COVID-19 virus and distort its structure along with IR treatment which further results in hampering the viral survival and reproducibility(Yang 2021).

Various nanoparticles such as gold and carbon quantum dots (CQDs) are excellent options for interacting with the virus as well as averting entry within the cells due to the large surface area as well as a broad range of functional groups. CQDs possess a diameter 10 nm approx. and good water solubility, making it an ideal applicant for conquering coronavirus, due to easy entry through endocytosis and preventing mRNA replication (Wang et al. 2019; Iannazzo et al. 2018).

Gold nanoparticles using extracts impart additional advantages such as being eco-friendly, non-toxic, cost-effective, and easily accessible. Research performed so far revealed that gold nanoparticles can be stabilized with few polymers (bio-compatible) that might act as antiviral agents against HIV 1, FMDB, diarrhea, dengue, H1N1, H3N2, and H5N1 virus (Medhi et al. 2020). Silver, iron, mesoporous silica (Wang et al. 2017; Lara et al. 2010; Rojas et al. 2020; Rai et al. 2016) and organic particles such as Carbon nanotubes & Nanoparticles Graphene, Polymeric, Lipid-based, Dendrimers revolution in nanotechnology employing novel nanocarriers and magnetic nanoparticles (Comparetti et al 2018; Alidori et al. 2016; Mangum et al. 2006; Singh et al. 2019; Hennig et al. 2015; Figueroa et al. 2019; Pollock et al. 2010; Jain et al. 2011; Shah et al. 2017; Lembo et al. 2018; Li et al. 2005; Clayton et al. 2009; Itani et al. 2020; Williams & Corr 2013) have been documented in the treatment of Covid-19. The current strategies of nanoparticles used in the treatment of COVID-19 infection are shown in Table 7.

Table 7 Current strategies on nanoparticles
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Discussion

An epidemic of pneumonia that started in December 2019 (Wuhan-China) has been well known to be due to novel coronavirus, which has been named later as COVID-19. The virus is extremely contagious and results in pandemic situations due to the lack of any medicine for prophylaxis as well as treatment.

Subsequently, searching the effective prophylactic and therapeutic strategies for the management of the disease is still continuing. Furthermore, the emergency requirement of drugs leads to the repurposing of drugs which has been mentioned in this article. We illustrated categorized response based on infection and contiguity stages of diseases among the human population. Despite the fact that until now no medicine system provides clinically proven treatment for COVID-19, continuous research is ongoing searching for the effective treatment for COVID-19(Fig. 10)(Silva et al. 2020; Sadlon et al. 2010; Rosa et al. 2020; Jin et al. 2020).

Fig. 10
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Drugs and their effectiveness in the treatment of mild to moderate infection

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Moreover, vaccines, anti-viral drugs, and antibiotics possess the gold standard for the current preventive measures for different epidemic disorders until now. Furthermore, problems related to developing dispensing, side effects, storage conditions, mutations, and antibiotic-resistant microbes should also be taken into considerations. Novel approaches for communicable diseases are absolutely required and the WHO also mentioned that at the time of the Ebola outbreak in 2014. The expert committee stated that it’s unethical to suggest unproven intercession with unknown efficiency as well as adverse effects as promising treatment/prophylaxis. It should be taken into consideration that it’s not only COVID-19, but there are also other viruses as well as diseases for their vaccines, and clinically proven treatment is not available. Therefore, innovative research, as well as technique, is absolutely required for providing effective medication to society (Fig. 11)(Veronese et al. 2020; Reyes et al. 2020; Michael and Thompson 2020; Cox et al. 2021; Furuta et al. 2017; Cristian et al. 2020; Chaccour et al. 2021).

Fig. 11
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Drugs and their effectiveness in severe infection of SARS COV-2

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Challenges and issues observed during vaccine development

Vaccine development takes an average of 10–15 years, and compressing it to just 15 months has its own set of drawbacks and issues. Combining stages to accelerate vaccine development necessitates testing on smaller groups. This is a major issue because, if the vaccine is made available to the general public, unexpected adverse effects may develop in bigger groups that were previously undetected in smaller groups. Furthermore, if all individuals with comorbidities are not properly addressed in the design of clinical trials, unexpected adverse effects may be discovered in those groups once the vaccine is ready for general use. Vaccines would be examined for similar adverse effects in the broader population under post-marketing surveillance. It’s uncertain how mRNA vaccines will be developed since in past researches. Nucleic acid–based vaccines like DNA and RNA have failed to generate viable vaccinations for human diseases in the past. Because lipid nanoparticles are temperature sensitive, scaling up production may be difficult. Pre-existing adenovirus immunity is a concern, particularly for vaccine candidates that utilize human adenoviruses, such as CanSino’s Ad5 vaccine, since it may reduce the vaccine’s immunological response (Sharma et al. 2020).

In order to meet pandemic demand, rapid large-scale vaccine production remains a challenge fraught with uncertainties. Because phase 3 trials need more than 30,000 individuals and are performed later in the study phase, there is a high chance that there will be fewer instances of COVID-19 at that time, requiring HCTs. Despite the fact that HCTs have been utilized in the past, they may pose a higher risk for COVID-19 due to a lack of understanding of the disease's genesis and the absence of a feasible treatment. As an alternative to HCTs, several vaccine candidates have taken advantage of transmission rate differences by starting phase 3 trials in countries with a higher SARS-CoV-2 infection rate to ensure that a significant number of patients can participate. Vaccines against the virus may be ineffective due to the virus’s mutations. However, given the urgent need for a COVID-19 vaccine to be accessible globally, being concerned about and analyzing such risks should not prevent the public introduction of otherwise safe and effective vaccines (Sharpe et al. 2020, Morris 2020, Sharma et al. 2020).

Future perspective

The COVID-19 pandemic is still a global health issue that has impacted a vast number of people. From December 2019 onwards, most nations around the world have recorded a substantial number of COVID-19 cases. There are currently no effective vaccinations or medications available to prevent COVID-19 infection. To address these health issues, various research groups are working to determine the most effective treatment for COVID-19 by delivering FDA-approved antiviral medicines such as oseltamivir, ritonavir, remdesivir, ribavirin, and favipiravir, among others. Simultaneously, scientists are concentrating on the creation of several types of vaccinations that can prevent COVID-19 infection. According to the survey results, research will continue until acceptable drug candidates and vaccines are found based on pathological conditions, physiology, clinical symptoms, diagnosis, and public health emergencies.

Conclusion

Keeping in view of this epidemic, we’re still waiting for precise COVID-19 treatment and care. Although a few medicines, such as remdesivir, ribavirin, and favipiravir, are prescribed for the therapy, it is difficult to employ them specifically for the treatment of COVID-19 infection due to a lack of clinical data. These medicines were discovered to have a high affinity for the COVID-19 primary protease. Antimalarial medications like chloroquine and hydroxychloroquine, on the other hand, had a strong binding affinity with the SARS spike glycoprotein and the ACE2 complex. Vaccination has begun in India, although clinical data on safety and efficacy will not be available for some time. Even after immunization, everyone should be upbeat and follow the instructions to the letter. It’s also been noted that we’re dealing with not only COVID-19 but also its fear, particularly in India.