Vol. 001, Issue 01, Pg. No.: 001 – 020 Review Article

The Journal of Pharmaceutical Sciences and Medicinal Research

A COMPREHENSIVE OVERVIEW ON THE MOST RECENT TRENDS IN COVID-19 DIAGNOSIS, TREATMENT OPTIONS AND VACCINE DEVELOPMENT STATUS

Jayendrakumar Patel1, Shalin Parikh2, Shwetaben Patel3 1, 3 Shree SK Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana, Gujarat, India – 384012 2 Shree Sarvajanik Pharmacy College, Near Arvind Baug, Gujarat, India - 384001 1 Corresponding Author: Jayendrakumar Patel, Address: Shree SK Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana, Gujarat, India – 384012. *Corresponding author’s email: [email protected] Received On: 14 May 2021 ARTICLE Final Revision Revised On: 26 May 2021 HISTORY Accepted On: 27 May 2021 DOI 10.53049/tjopam.2021.v001i01.001

Abstract The global pandemic produced by the novel severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), which was first appeared in Wuhan, China, in December 2019 and which then spread rapidly, made it difficult to find or develop effective medications for its prevention and treatment. Therefore, the first stage is necessitating the use of a precise and quick diagnostic method to detect SARS-CoV-2 infected patient followed by effective patient isolation and the commencement of early treatment, which can range from supportive therapy to specialised medications such corticosteroids, antiviral medications, antibiotics, and the recently introduced convalescent plasma. Despite the extraordinary developments in advanced medicinal system, no confirmed viable medicines exist at this time. Rapid research on SARS CoV-2 epidemiology has led to the discovery of certain new targets for prospective therapeutic treatments. Many therapeutic options have been evaluated, and clinical studies are proceeding at a breakneck speed. However, there is a lot of room for more study into finding cost-effective and safer medicines, vaccinations, and measures to ensuring that COVID-19 preventive and treatment programmes are available to everyone. The goal of this study is to compile all of the current advancements in the worldwide medical system in the fight against COVID-19. Keywords: Coronavirus, COVID 19, Diagnosis, Therapy, Vaccine, Antiviral, Treatment, Mechanism

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The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al

1.0 INTRODUCTION Sore throat, new loss of smell or taste, nausea or vomiting, COVID-19 was discovered in Wuhan, China, in December of and diarrhoea [5]. Pneumonia, respiratory failure, cardiac 2019. The virus that causes COVID-19 is the severe acute issues, liver difficulties, septic shock, and death can all be respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel caused by the virus. A condition known as cytokine release virus that causes respiratory illness in humans and can be syndrome or a cytokine storm may be the source of many passed from person to person. Many patients were linked to a COVID-19 problems. This happens when an infection causes big seafood and live animal market early in the outbreak, but your immune system to release inflammatory proteins called later cases with no relationship to the market showed person- cytokines into your bloodstream. They have the ability to kill to-person transmission of the disease. Additionally, cases tissue and harm your organs [6]. The incubation period is have been exported as a result of travel [1]. predicted to be between 2 and 14 days, with a median of 5 COVID-19 is mostly spread by respiratory droplets from days. It's vital to keep in mind that some people get infected person to person. When someone with COVID-19 sneezes, yet don't show any symptoms or feel ill [5]. coughs, or talks, droplets are emitted. Infectious droplets can The main aim and objective of the present review article is to fall into the mouths or nostrils of close persons, or be provide a comprehensive overview of the most recent trends breathed into the lungs. The World Health Organization in COVID-19 diagnosis, treatment options and vaccination (WHO) recommends keeping a physical distance of at least 1 development status. metre (3 ft) between people to avoid infection [2], whereas 2.0 HOW SARS-COV-2 INFECTED? the Centers for Disease Control and Prevention (CDC) SARS-CoV-2 is a single-stranded RNA virus that infects recommends keeping a physical distance of at least 1.8 cells via its surface spike glycoproteins (S proteins). S metres (6 ft). When people cough or talk, respiratory droplets proteins interact to the human angiotensin converting can land on hands, objects, or surfaces around them, and enzyme 2 receptor with a high affinity [7, 8]. The viral S people can become infected with COVID-19 by contacting protein has two regions: S1 and S2. S1 is responsible for droplets on hands, objects, or surfaces and then contacting attaching to the host cell receptor, whereas S2 is responsible their eyes, nose, or mouth. COVID-19 can be transmitted for membrane fusion. Virus particles enter cells by receptor- through the droplets of people who have minor symptoms or mediated endocytosis, which involves host cell receptors and don't feel sick, according to new research [3]. Long-distance endosomes, after interacting with receptors [7, 9]. It aerosol transmission of SARS-CoV-2, as seen with measles synthesises viral polyproteins that encode for the replicase- or tuberculosis, is not supported by current data. COVID-19, transcriptase complex once it enters the cell. The virus then like many respiratory viruses, is susceptible to short-range uses RNA dependent RNA polymerase to make its RNA aerosol inhalation. However, epidemiologic characteristics (RdRp). The production of structural proteins leads to the make it difficult to distinguish this from "droplet" assembly and release of viral particles [7, 10, 11]. S protein transmission. Short-range transmission is a potential, binding to the ACE2 receptor has been shown to trigger a especially in crowded medical wards and settings with negative feedback loop in SARS-CoV and presumably insufficient ventilation [4]. Certain medical operations can SARS-CoV-2, resulting in the downregulation of ACE2 produce fine aerosols, which should be avoided wherever expression. The decrease in ACE2 causes angiotensin I, its possible. substrate, to boost its related enzyme, angiotensin-converting COVID-19 has been linked to a wide range of symptoms. enzyme (ACE) [11]As a result of increased ACE activity, Fever or chills, Cough, Shortness of breath or difficulty high levels of angiotensin II and overactivated AT1 receptors breathing, Fatigue, Headache, Nasal congestion or runny (Angiotensin II receptor type 1) develop, resulting in lung nose, Fever or chills, Cough, Shortness of breath or trouble damage [7, 12]. SARS-CoV-2 can impact a variety of organs breathing, Fatigue, Headache, Nasal congestion or runny and cause a variety of clinical symptoms since ACE2 nose, Aches and pains in the muscles or throughout the body receptors are broadly distributed [13].

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Each of the tests listed above is important and 4.0 HOW TO DIAGNOSE COVID-19? complementary at different stages of the COVID-19 Fever, cough, and malaise have been the most common pandemic. symptoms of SARS-CoV-2 infection. Based on the patient's 3.0 HOW TO INDETIFY IF IT’S A COVID 19, age and comorbidities, further symptoms targeting the COLD, FLU OR ALLERGIES? respiratory, gastrointestinal, and urinary systems have been The following table shows comparative symptoms to identify recorded [14,15]. SARS-non-specific CoV-2's clinical COVID 19 from Cold, Flu and Allergies [6]. manifestation necessitates timely detection in order to Table 1: Comparative Symptoms to identify COVID 19 from effectively control this raging disease. Sensitive and specific Cold, Flu and Allergies diagnostic technologies, such as gene sequencing, electron Cold Vs Flu Vs Allergies Vs COVID-19 microscopy, and cell culture procedures, can help with this Types of COVID-19 Flu Cold Allergies [14,16]. The most frequent quick diagnostic technique for Symptoms identifying SARS-CoV-2 is real-time reverse transcriptase- High (100- 102 F), Can polymerase chain reaction (RT-PCR), which combines the Fever Common Rare Never last 3-4 principles of transcription and amplification, resulting in a days high specificity rate [14,17]. Depending on the clinical Headache Can be present Intense Rare Uncommon manifestation of the patients, viral detection specimens range Usual, General Can be present often Slight Never from nasopharyngeal and oropharyngeal swabs to broncho- aches, pains severe alveolar lavage, sputum, stool, urine, and blood [14,18]. Intense, Personal protective equipment (PPE) is required because Tiredness Common starts early, Mild Sometimes c swab collection poses a high transmission risk due to close Usual gone contact between the health worker and the suspected patient, Longhaul Can be present in 2-3 Never Never exhaustion 2) Storage and transportation should be done effectively to weeks avoid false-negative and false-positive results, and 3) In Stuffy/runny Has been Sometimes Common Common nose reported individuals with a low platelet count, swab collection should Has been be done with caution because it can cause easy bruising and Sneezing Sometimes Usual Usual reported bleeding at the collection sites [14,19,20]. Has been Sore throat Common Common Sometimes 4.1 Type of Testing reported Common, There are mainly 4 types of diagnostic tests for detecting a Mild to Cough Common can become Sometimes moderate current or past viral infection, namely RT-PCR test, Antigen severe Screening, Nucleic Acid Test, Antibody Test [14]. Loss of smell Has been Sometimes Sometimes Never and taste reported 4.1.1 Nucleic Acids Amplification Test (NAAT) Can It is the gold standard test for detecting SARS-CoV-2 at the Rash Can Happen Rare Rare Happen moment. It detects viral RNA from samples acquired at Can Can Can Pink Eye Can Happen specimen sites using Reverse Transcription Polymerase Happen Happen Happen Has been Sometimes Chain Reaction (RT-PCR) [21]. RT-PCR is a sensitive and Diarrhea Never Never reported in children specific technology that utilises successive binding on Rare, genetic material that targets a specific pathogen of interest In more except for Shortness of and amplifies that specific region in an optimum reaction serious Rare Rare those with Breath infections allergic setting with each cycle [22]. Each cycle produces a asthma fluorescent emission, and the test is declared positive when In more In more the intensity reaches a certain level. Because the Chest Pain serious serious Rare Rare infections infections amplification and analysis are done at the same time, the

The J. Pharm. Sci. and Med. Res. (001) (01) (001-020) Page | 3 The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al false-positive situations are exaggerated. N, E, and RNA 4.1.4 Antibody test dependent RNA polymerase are among the SARS-CoV-2 It detects particular antibodies (IgG and IgM) produced in genes that have been targeted thus far (RdRp). It will be response to SARS-CoV-2 infection in the host's serum, regarded affirmative if these genes are found in the test [23]. plasma, or whole blood. It is critical for diagnosing the The test's processing time is estimated to be around 45 illness in its later stages and identifying persons who are minutes, and it is currently the fastest [24]. With their latest immune to the sickness. It can also be used to track the advancement in technology, Abbott's ID NOWTM targets evolution of the disease and to create a vaccination [31]. The the RdRp gene and validates the test in less than 13 minutes. enzyme-linked immunosorbent assay (ELISA), the This has been granted FDA emergency use authorisation for chemiluminescence assay (CLIA), and the luminescence usage in outbreak epicentres. The test's main drawback is assay (LFA) are some of the most regularly used antibody that it can only analyse one sample at a time [25]. tests. The lateral flow assay is a new, low-cost, and easily 4.1.2 Computed Tomography Scan (C.T. Scan) accessible antibody detection test for SARS-CoV-2. When Due to low viral load and limited availability of test kits in compared to RT-PCR, it is highly specific but less sensitive. various regions of the world, it has a low sensitivity for early This approach can rapidly detect severe instances with a high identification of the disease. These characteristics have led to viremic load, which can serve as a warning sign for patients the acceptance of C.T. chest as a supplementary diagnostic with a poor prognosis [32]. test in individuals suspected of having COVID-19 [26]. CT 4.2 Scenarios for Testing Overview scan has played a critical role in the diagnosis and treatment 4.2.1 Diagnostic Testing of COVID-19 since it was first included in the guidelines for When a person displays signs or symptoms compatible with the disease's diagnosis and therapy. The mixed pattern is the COVID-19, or when a person is asymptomatic but has most common pattern of abnormalities found following the recently known or suspected exposure to SARS-CoV-2, onset of symptoms, followed by ground glass opacities. The diagnostic testing is undertaken to identify current infection. lesions are usually bilateral and sub-segmental in most cases. The following are some examples of diagnostic testing [33, These aberrant findings, however, may be non-specific 34]: because they overlap with viral pneumonia of many  People who present to their healthcare provider with etiologies [27]. symptoms similar with COVID-19 will be tested. 4.1.3 Antigen Screening  As a result of contact tracing operations, persons are From nasopharyngeal and oropharyngeal swabs, this assay being tested. detects the presence of SARS-CoV-2 nucleocapsid protein  People who have indicated that they have been exposed antigen on the viral surface [28]. Specific monoclonal to someone with a confirmed or suspected case of antibodies (MAb) bind to specific viral antigens in fluid COVID-19 are being tested. samples in this assay. Calorimetric enzyme immunoassay,  People who attended an event where another attendee improved chemiluminescent immunoassay, and the most was later diagnosed with COVID-19 were tested. contemporary, economical, quick, and user-friendly 4.2.2 Screening test fluorescence lateral flow assay can all be used to detect it Screening tests are used to identify infected persons who are (LFA). The structural proteins of the coronaviruses, such as asymptomatic and have no history of SARS-CoV-2 infection spike (S), membrane (M), envelope (E), and nucleocapsid (known, suspected, or reported). Screening aids in the (N), are the important foci in the SARS-CoV-2 virus for identification of undiscovered cases so that preventative subsequent antigen-based assays. Antigen-based tests, on the measures can be performed. The following are some other hand, are not considered a gold standard in the examples of screening [33, 34]: diagnosis of COVID-19 due to their lower detection  Employees are put to the test in the workplace. sensitivity and specificity than PCR [29,30].  Before or after a trip, a person is tested.

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 In a school or university context, students, instructors, 2020, the FDA issued an EUA for baricitinib to be used in and staff are tested. conjunction with remdesivir in COVID-19 patients who  Testing at home for people who don't have COVID-19 require supplemental oxygen or breathing support. Only use symptoms and haven't been exposed to someone who baricitinib with remdesivir if corticosteroids (such as has COVID-19. dexamethasone) are not an option, according to the National 4.2.3 Public health surveillance Institutes of Health. The goal of public health surveillance is to track the burden Not all remdesivir studies have yielded positive results. A of disease at the population level, as well as to describe comprehensive, randomised research published by the World illness incidence and prevalence. Surveillance testing is Health Organization (WHO) on October 15, 2020 indicated mostly utilised to gather data at the population level rather that remdesivir had little or no influence on death rates in than at the individual level. Individuals are not informed of hospitalised COVID-19 patients. Regardless of whether the findings of surveillance testing. Surveillance testing, as a patients received remdesivir or not, the death rate was around result, cannot be utilised to make individual health-care 11%. These findings have not yet been peer-reviewed. decisions or to take individual public-health actions like Researchers looked at nearly 600 hospitalised patients with isolation or quarantine [33]. Wastewater surveillance is one significant COVID-19 symptoms in a randomised, open- form of surveillance testing. label study and found conflicting results. Some patients 5.0 WHAT ARE THE CURRENT THERAPEUTIC received remdesivir for 5 days, some for 10 days, and some TREATMENT OPTION AVAILABLE AS WELL for none (the control), and they were all evaluated on a 7- AS UNDER INVESTIGATION FOR COVID 19? point scale on day 11. People who took the medicine for five 5.1 Antiviral Agents days scored higher on the scale than those who didn't, 5.1.1 Remdesivir [35] although it's unclear if the difference was clinically Remdesivir is an antiviral that is administered in the hospital significant. No change was found between individuals who via intravenous (IV) infusion. The FDA approved remdesivir took remdesivir for 10 days and those who did not. There (Veklury) for the treatment of COVID-19 in patients aged 12 was also no difference in the groups that received remdesivir and up who require hospitalisation on October 22, 2020 [36]. for 5 days versus 10 days. For treating people with moderate The approval was largely based on the results of three COVID-19 symptoms, more study is needed. investigations, all of which were good. Remdesivir was also found to be ineffective in a Chinese trial Various recommendations have been made about the use of of 236 patients with COVID-19. (This was a double-blind, remdesivir. Due to a lack of data, the National Institutes of randomised trial, which is the gold standard in clinical Health (NIH) supports using remdesivir for select COVID-19 studies.) A group of patients in the research who took hospitalised patients, but the World Health Organization remdesivir within 10 days after exhibiting symptoms healed (WHO) does not suggest it for any COVID-19 patients. slightly faster than those who received a placebo, according Remdesivir is also being researched in conjunction with to one analysis. This difference, however, was not other drugs. According to one study, COVID-19 patients statistically significant, implying that it could have happened who received both remdesivir and baricitinib (Olumiant) by coincidence. When all patients in the study (regardless of recovered 1 day quicker than those who just received when they received remdesivir) were compared to placebo, remdesivir (7 days vs. 8 days). Additionally, when both there was no difference in time to improvement. Larger drugs were taken concurrently, patients had a 30% higher investigations are needed to corroborate the findings, chance of clinical improvement at day 15. In comparison to according to the experts. patients who only received remdesivir, individuals who 5.1.2 Molnupiravir [37] received both drugs were less likely to require ventilator or Molnupiravir (MK-4482 [formerly EIDD-2801]; Merck) is a die on day 29. (23 percent vs. 28 percent ). On November 19, prodrug of the nucleoside derivative N4-hydroxycytidine and

The J. Pharm. Sci. and Med. Res. (001) (01) (001-020) Page | 5 The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al is an oral antiviral medication. It causes antiviral effects by lopinavir and ritonavir, two antiviral drugs. These antiviral causing copying errors in the SARS-CoV-2 virus's RNA medicines may have some effect against SARS and MERS, replication. According to preliminary findings from the phase according to in vitro and clinical trials of individuals who 2a dose-ranging MOVe-OUT study (n = 2020), 24 percent of have previously taken them (infections caused by other patients in the placebo group remained culture positive for coronaviruses). There is a scarcity of data about Kaletra's use SARS-CoV-2 10 days after symptom onset, whereas no in COVID-19 [35]. infectious virus could be recovered in any molnupiravir- There was no difference between using Kaletra and not using treated outpatients at study day 5. The inpatient molnupiravir it in a randomised study of 199 adults hospitalised with experiment (MOVe-IN) has been terminated, but a phase 3 COVID-19 in terms of how long it took for patients to trial in outpatients with at least one risk factor for poor improve. Another short trial compared Kaleta alone to outcomes (e.g., age, obesity, diabetes) will continue with Kaletra in combination with interferon beta-1b and ribavirin patients receiving 800 mg orally twice daily [38]. in 127 persons with mild COVID-19 symptoms. They 5.1.3 Favipiravir [37] discovered that those who received all three treatments Favipiravir (Avigan; Appili Therapeutics) is an antiviral that improved and eradicated the virus more quickly (7 days) than has been authorised in Japan for the treatment of influenza. those who just received Kaletra (12 days). The National In Russia, it is licenced for the treatment of COVID-19. Institutes of Health presently advises against using Kaletra Favipiravir inhibits RNA polymerase, which is required for for COVID-19 [35]. viral replication, in a targeted manner. In Russia, researchers 5.1.5 Umifenovir conducted an adaptive, multicenter, open label, randomised, Outside of the United States, umifenovir (Arbidol) is a flu phase 2/3 clinical trial of favipiravir versus standard of care I medicine. As previously stated, it was not as effective as hospitalised patients with mild COVID-19. The virologic favipiravir in helping patients recover in a Chinese research. response to both favipiravir dosage regimens was identical. Another research of 81 individuals looked at how long it On Day 5, viral clearance was achieved in 25/40 (62.5 took for patients to test negative for the coronavirus after percent) of favipiravir-treated patients compared to 6/20 (30 they first developed symptoms, and found no difference percent) of standard-care patients (p = 0.018). On Day 10, between those who received umifenovir and those who did viral clearance was achieved in 37/40 (92.5%) of favipiravir- not. However, it appears to be more effective than Kaletra at treated patients, compared to 16/20 (80%) in the standard- helping COVID-19 patients remove the virus. The virus was care group (p = 0.155). [39] not discovered in any of the 50 patients who got umifenovir In the United States, the phase 3 PRESECO (Preventing after 14 days in a small study of 50 persons. The virus was Severe COVID Illness) research is examining the drug's still detectable in nearly half of the Kaletra patients [35]. effectiveness in preventing disease development and 5.1.6 Oseltamivir Phosphate hospitalisation in individuals with mild-to-moderate Oseltamivir Phosphate (Tamiflu) is an antiviral drug used to symptoms. Asymptomatic patients with direct exposure treat influenza (flu). The findings of a hospital in Wuhan, (within 72 hours) to an infected individual will be studied in China, were not encouraging. Tamiflu was given to 124 of the phase 3 PEPCO (Post Exposure Prophylaxis for COVID- the 138 hospitalised patients, along with additional 19) trial. A study of patients in hospitals is also underway. treatments. 85 patients (62%) were remained hospitalised at [40,41] In addition, the phase 2 CONTROL project is the end of the trial, and 6 had died. Nonetheless, Tamiflu is examining its efficacy in preventing COVID-19 outbreaks in now being studied in combination with other coronavirus Canadian long-term care settings. [42] treatments in a number of clinical trials [35]. 5.1.4 Lopinavir and Ritonavir 5.1.7 Galidesivir Kaletra (lopinavir/ritonavir) is a combination of lopinavir Galidesivir is a novel medicine in development for a range of and ritonavir. Kaletra is an HIV treatment that combines viral diseases, however it has not yet been authorised for

The J. Pharm. Sci. and Med. Res. (001) (01) (001-020) Page | 6 The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al human use. Galidesivir is undergoing clinical testing in Inc. The medication appears to target small interfering Brazil [35]. RNA in vitro (siRNA). RNA interference (RNAi) is a 5.1.8 Other Investigational Antivirals for COVID-19: type of gene silencing that occurs naturally in cells. By The following are the list of other antiviral drug which are silencing messenger RNA, siRNA molecules mediate under investigational stage for COVID 19 [37]. RNAi function (mRNA). Disease-causing proteins are 1. IV SARS-CoV2-3CL protease inhibitor PF-07304814 encoded by mRNA, which is a genetic precursor. The (Pfizer) in phase 1b clinical development in hospitalised businesses intend to move forward with the medication patients [43]. candidate's development as an inhalational formulation 2. Oral SARS-CoV2-3CL protease inhibitor PF-07321332 [49]. (Pfizer) is in phase 1 clinical development [44]. 8. Emetine hydrochloride (Acer Therapeutics): Emetine 3. Ensovibep (MP0420; Molecular Partners and Novartis) is hydrochloride, the active element in ipecac syrup (given a designed ankyrin repeat protein (DARPin) with three orally to cause emesis), has been developed as an antigen-binding sequences that bind to the same epitope injectable to treat amebiasis. Clinical trials for viral area inside the SARS-CoV-2 spike glycoprotein RBD. hepatitis and varicella-zoster virus infection have been Starting in mid-2021, a dose-finding trial in symptomatic done. Zika, Ebola, Rabies Lyssavirus, CMV, HIV, outpatients will be conducted [45]. influenza A, echovirus, metapneumovirus, and HSV2 4. Rintatolimod (Poly I:Poly C12U; Ampligen; AIM have all been shown to be potent against DNA and ImmunoTech) is Toll-like receptor 3 (TLR-3) agonist RNA-replicating viruses in vitro. It's also a powerful being studied by the National Institute of Infectious inhibitor of a variety of coronaviruses with different Diseases (NIID) in Japan and the University of Tokyo as genetic profiles. An adaptive design phase 2/3 a potential treatment for COVID-19. In December 2020, randomised, blinded, placebo-controlled multicenter a clinical trial for myalgic encephalomyelitis/chronic trial in high-risk symptomatic people with confirmed fatigue syndrome (ME/CFS), often known as the "Long COVID-19 who do not require hospitalisation is being Haulers" illness, was launched. It's an antiviral with planned to assess the safety and antiviral activity of immunologic characteristics that's broad-spectrum [46]. emetine [50]. 5. Bemcentinib (BerGenBio ASA) is a selective oral AXL 9. AT-527 (Atea Pharmaceuticals) is an orally kinase inhibitor that has been shown to have significant administered purine nucleotide prodrug that inhibits the antiviral efficacy in preclinical models against a variety RNA polymerase enzyme. It shows antiviral action of enveloped viruses, including Ebola and Zika. This against numerous enveloped single-stranded RNA has now been expanded to include SARS-CoV-2. As viruses, including human flaviviruses and part of the UK's Accelerating COVID-19 Research and coronaviruses, both in vitro and in vivo. The FDA has Development (ACCORD) project, a phase 2 study of approved an IND for a phase 2 trial in individuals bemcentinib in hospitalised COVID-19 patients is hospitalised with mild COVID-19 [51]. planned [47]. 10. Trabedersen (OT-101; Mateon Therapeutics, Oncotelic) 6. Plitidepsin (Aplidin; PharmaMar) is a member of the is an antisense oligonucleotide that blocks the didemnins chemical class. According to in vitro expression of TGF-beta2. Viral replication necessitates research from Spain, plitidepsin may target EF1A, cell cycle arrest, which is achieved by viral TBF-beta which is important for virus replication and induction. In India and Peru, phase 2 trials have begun transmission [48]. [52]. 7. VIR-2703 (ALN-COV; Vir Biotechnology Inc and 11. Antiviral agent stannous protoporphyrin (SnPP; RBT-9; Alnylam Pharmaceuticals, Inc) is a drug developed by Renibus Therapeutics) in phase 2 trial for COVID-19 Vir Biotechnology Inc and Alnylam Pharmaceuticals, treatment in individuals at high risk of deteriorating

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health due to age or concomitant diseases (eg, kidney or 5.2 Antimalarial Drugs cardiovascular disease) [53]. Both hydroxychloroquine and chloroquine have been used to 12. Antiviral/anti-inflammatory agent Antroquinonol treat malaria and autoimmune diseases such as rheumatoid (Hocena; Golden Biotechnology Corp): In both cell and arthritis and lupus for decades. Although a few small studies animal studies, it reduces viral nucleic acid replication suggested that they might be useful for treating COVID-19 in and viral protein production. When mice with severe hospitalised patients with mild instances, national health inflammation were given antroquinonol, it was found to agencies (such as the FDA) now agree that prevent organ and tissue damage. The IND for a phase hydroxychloroquine and chloroquine do not function for 2 clinical trial in patients with mild-to-moderate preventing or treating COVID-19. The National Institutes of COVID-19 pneumonia has been approved by the FDA Health advises against using them for COVID-19. Here you [54]. can find more information on hydroxychloroquine and 13. AI Therapeutics' Apilimod dimesylate (LAM-002A): chloroquine research [35]. PIKfyve, a lipid kinase enzyme, is inhibited. It 5.3 Antibiotics interferes with SARS-CoV-2 virus entrance and 5.3.1 Azithromycin. trafficking in cells through disrupting lysosome Azithromycin is a type of antibiotic used to treat bacterial functioning. In late July 2020, a phase 2 trial will begin infections like bronchitis and pneumonia. It has been proven at Yale University [55]. to have some in vitro activity against viruses such as 14. Remdesivir inhalation (Gilead Science): In late June influenza A and Zika, but not against the MERS-causing 2020, a phase 1b trial of inhaled nebulized remdesivir coronavirus. For COVID-19, one study looked at will begin to see if it can be utilised as an outpatient azithromycin in combination with hydroxychloroquine. They treatment and at early stages of disease [56]. claimed that 93 percent of patients had cleared the infection 15. Brequinar (Clear Creek Bio, Inc) is a dihydroorotate after 8 days, but there was no control group, so we don't dehydrogenase (DHODH) inhibitor that can be used know if people would have cleared the infection on their own orally. In vitro, it has been shown to suppress viral if the drugs hadn't been used. When azithromycin and replication of SARS-CoV-2 as well as a wide range of hydroxychloroquine are used together, there are concerns RNA viruses. The DHODH enzyme is inhibited, about possibly serious adverse effects. The National resulting in pyrimidine depletion and a reduction in the Institutes of Health now advises against using azithromycin mitochondrial electron transport required for viral to treat COVID-19. [35] multiplication. In November 2020, the phase 2 trial 5.4 Steroids (CRISIS2) in hospitalised patients began [57]. 5.4.1 Dexamethasone 16. Brilacidin (Innovation Pharmaceuticals) is Antiviral, Dexamethasone is a common corticosteroid (steroid) anti-inflammatory, and antibacterial host defence medicine that has been used to treat a variety of health protein mimic. Its anti-inflammatory properties are disorders for many years, including autoimmune diseases linked to the suppression of proinflammatory cytokines and allergic reactions. Many drugs, including such as IL-6, IL-1beta, TNF-alpha, and others. Antiviral dexamethasone, are being studied in RECOVERY, a activity against SARS-CoV-2 has been demonstrated in randomised clinical trial in the United Kingdom, to vitro [58, 59]. investigate if any are useful against COVID-19. Researchers 17. Sangivamycin (TNX-3500; Tonix Pharma) is under discovered that the 2,104 COVID-19 hospitalised patients phase of preclinical research. In laboratory-based who received a modest daily dose of dexamethasone (either studies, broad-spectrum antiviral activity was by mouth or IV injection) had a reduced death rate at day 28 demonstrated against the coronaviruses SARS-CoV-2 than the 4,321 patients who did not (23 percent versus 26 and MERS-CoV [37]. percent , respectively). This was a considerable difference.

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Patients who were on a ventilator or needed supplemental plasma), so it's unclear if the difference in death rates was oxygen seemed to benefit the most from the medicine. Those due to the treatment or something else. Patients who received with less severe symptoms received no improvement. convalescent plasma with greater antibody levels had a lower Furthermore, fatality rates were lower in hospitalised patients death rate than those who received plasma with lower who took one of three distinct corticosteroids — antibody levels [61]. dexamethasone, hydrocortisone, or methylprednisolone — A group of experts from the National Institutes of Health compared to those who took none, according to a meta- (NIH) disagreed with the FDA's conclusion, claiming that analysis that looked at outcomes from seven distinct trials there is insufficient data to prescribe convalescent plasma for (32 percent vs. 40 percent) [35]. COVID-19 [62]. 5.4.2 Methylprednisolone Other studies on convalescent plasma have yielded mixed Patients' pulmonary involvement, oxygen saturation, results. Researchers in China revealed that 10 patients with dyspnoea, heart rate, respiratory rate, temperature, and severe COVID-19 symptoms (fever, cough, shortness of inflammatory markers (e.g. CRP and IL-6 serum levels) all breath, and chest pain) healed dramatically within three days improved significantly after receiving methylprednisolone at of receiving treatment. The group who got convalescent the start of the early pulmonary phase of illness, suggesting plasma improved their health more than the historic control that methylprednisolone could be an effective therapeutic group (a random sample of individuals who had previously agent for hospitalised severe asthmatics [60]. been hospitalised for COVID-19) [63]. In a separate research 5.5 Biological Substance of 103 patients in China, no difference in clinical 5.5.1 Convalescent Plasma improvement was seen between those who received The FDA approved an Emergency Investigational New Drug convalescent plasma and those who did not. At 28 days, (eIND) application for the use of convalescent plasma to there was no difference in death rates, and persons in both treat COVID-19 patients on March 24, 2020. Plasma is the groups were discharged from the hospital in about the same liquid component of blood that transports blood cells across period of time [64]. the body. People who have recovered from COVID-19 have The studies employed diverse dosage and timing, and the their plasma collected as convalescent plasma. It is then study techniques were of low quality, according to a review given to someone who is infected with the coronavirus. of 8 convalescent plasma investigations with a total of 32 Antibodies present in convalescent plasma are suggested to subjects. Furthermore, some research found a benefit while aid in the fight against coronavirus infection. The FDA others did not [65]. issued an emergency use authorization (EUA) for 5.5.2 Monoclonal antibodies (MABs) convalescent plasma for hospitalised COVID-19 patients on Antibodies are proteins that the immune system produces to August 23, 2020. This does not imply that convalescent aid in the fight against infection. They bind to foreign plasma has been approved or proven as a COVID-19 pathogens such as viruses and aid in their destruction. treatment, but it does make it easier for providers to obtain Antibodies generated in a lab are known as monoclonal convalescent plasma if they believe it is worth a try [35]. antibodies (MABs). Because natural antibodies might take This decision was made based on preliminary findings from weeks to produce, MABs can help the body fight infections a Mayo Clinic research that included over 35,000 faster. Both Eli Lilly and Regeneron are working on MABs hospitalised COVID-19 patients who were given the therapy. for COVID-19, which are currently known as bamlanivimab The paper has not yet undergone peer review. The death rate (LY-CoV555) and REGN-COV2, respectively. Both was decreased at day 7 for those who received convalescent businesses submitted EUAs for their medicines in early plasma within 3 days of diagnosis than those who received it October, and the FDA approved them in November. after 4 or more days. There was no control group to compare AstraZeneca is also beginning research on AZD7442, a long- this to (i.e., patients who did not receive any convalescent acting antibody combination. VIR-7831 and the combination

The J. Pharm. Sci. and Med. Res. (001) (01) (001-020) Page | 9 The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al of BRII-196 and BRII-198 are two other MABs in rates of hospitalisation and death on day 29 than those who development [35]. did not. 5.5.2.1 Bamlanivimab (LY-CoV555) 5.5.2.3 Casirivimab and imdevimab (REGN-COV2) Bamlanivimab is a monoclonal antibody that prevents the REGN-COV2 has been dubbed a "antibody cocktail" since it SARS-CoV-2 virus from infecting human cells. In an early is made up of casirivimab and imdevimab, two monoclonal study, Eli Lilly found that individuals with mild to moderate antibodies. REGN-COV2 lowered viral load and eased COVID-19 who received bamlanivimab were less likely to symptoms sooner in individuals with COVID-19 who were be hospitalised than those who did not (2 percent were not hospitalised, according to a press statement from hospitalised vs. 6 percent , respectively). They put three Regeneron. The findings were based on the results of the first different doses to the test. The 2,800 mg dose had helped 275 patients, who were given either 2.4 grammes of REGN- clear the virus faster by day 11, but the lower and higher COV2, 8 grammes of REGN-COV2, or placebo, and whose dosages had not – this finding, however, is unlikely to be an symptoms disappeared after 6 days, 8 days, and 13 days, useful indicator of health because individuals who received a respectively. Patients who had not yet produced their own placebo were also able to clear some of the virus on their antibodies and had a higher level of virus in their bodies own. Eli Lilly tried a combination of two MABs, according benefited the most. These findings were later validated in a to another press release (bamlanivimab and LY-CoV016). news release containing data from an additional 524 patients. Patients who received the combination medication had a The research is still in progress, and the final results are not lower viral load on day 7 and were less likely to be admitted yet accessible. to the hospital than those who did not. These investigations The FDA approved casirivimab and imdevimab to be used are still in progress, and the final results aren't available yet. jointly to treat mild or moderate COVID-19 in patients aged The FDA approved bamlanivimab for the treatment of mild 12 and up who are at high risk of hospitalisation on or moderate COVID-19 in children aged 12 and up who are November 21, 2020. These drugs, including bamlanivimab, at high risk of hospitalisation on November 9, 2020. should be administered as an IV infusion in an outpatient Although bamlanivimab is administered by intravenous (IV) setting. Although casirivimab and imdevimab are being infusion, it should be done in an outpatient setting; it should examined in hospitalised patients, there is currently not be given to individuals who have already been admitted insufficient data to issue an EUA for their usage in this to the hospital for COVID-19. Indeed, the National Institutes setting. Despite the EUAs, the NIH indicated that there is of Health (NIH) has halted a trial of bamlanivimab in insufficient data to propose bamlanivimab, casirivimab, or hospitalised patients due to a lack of therapeutic benefit. imdevimab as the standard of therapy for COVID-19. Another source of concern is the possibility of quality control 5.6 Interleukin (IL) inhibitors difficulties at an Eli Lilly manufacturing plant where the 5.6.1 Tocilizumab antibody was produced. Tocilizumab is an IL-6 inhibitor that has been licenced for 5.5.2.2 Etesevimab and Bamlanivimab use in the treatment of rheumatoid arthritis and juvenile The use of bamlanivimab in combination with other idiopathic arthritis. (Both of these conditions are therapies is still being researched. The FDA granted an EUA inflammatory.) It acts by inhibiting the protein interleukin-6 on February 9, 2021 for the combination of bamlanivimab (IL-6), which is involved in our normal immunological and etesevimab to be used for mild or moderate COVID-19 responses. IL-6 is a cytokine (signalling protein) that usually in high-risk individuals aged 12 and up. At day 11, patients signals other cells to engage the immune system, but who received the combo therapy had less virus in their excessive activation can create problems. A cytokine storm, a bodies (lower viral load). This was not observed when potentially catastrophic problem in which the immune bamlanivimab was used alone. Additionally, patients who system goes wild and inflammation spirals out of control, is received both bamlanivimab and etesevimab had reduced one possible significant issue with an overactive immune

The J. Pharm. Sci. and Med. Res. (001) (01) (001-020) Page | 10 The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al system. People who are infected with COVID-19 may lotion or cream. Ivermectin can block SARS-CoV-2 from experience cytokine storms as their immune systems ramp up reproducing, according to an in vitro study[70]. Other small to battle the virus. Tocilizumab helps to quiet down the studies have been conducted, including a retrospective immune system by suppressing IL-6, and it's also thought to review of the medical records of 280 COVID-19 patients aid with cytokine storms [35]. who were admitted to a Florida hospital between March and Tocilizumab research began with a French trial that found May 2020. Ivermectin-treated patients died at a lower rate that persons who received tocilizumab were less likely to than those who did not (13 percent vs. 25 percent ). require ventilation or die [35]. Another Italian trial indicated However, this was not a well-designed trial, and patients may that individuals who received tocilizumab had a decreased have received additional therapies that influenced death rates. death rate, while both groups used ventilators at about the More research is required to determine whether the doses same rate [66]. tested are safe and efficient against the virus in humans [71]. Larger research have shown contradictory results, which may 5.8 Kinases Inhibitors be attributed in part to the various types of persons that Kinase inhibitors work in a similar way as IL-6 inhibitors in participated in the studies. In one research, tocilizumab was that they affect the immune system. Because they have the given to 3,924 patients in the hospital intensive care unit who ability to disrupt cytokine signalling pathways, they may be had severe COVID-19 (ICU). Patients who received useful in preventing cytokine storms. Some of them may also tocilizumab within the first two days of being admitted to the have antiviral properties. Many kinase inhibitors are used to ICU had a lower death rate (29%) than those who did not (41 treat cancer, but some are also licenced to treat inflammatory percent) [67]. Tocilizumab, on the other hand, was found to diseases like rheumatoid arthritis [35]. Baricitinib is a be ineffective in averting the need for a breathing tube selective JAK1/2 kinase inhibitor used in the treatment of (intubation) or mortality in 243 hospitalised individuals with rheumatoid arthritis and psoriatic arthritis. Its additional mild COVID-19. On day 28, 11% of patients who received cyclin-G-kinase binding action prevents the occurrence of tocilizumab were intubated or died, compared to 13% of immune-mediated ARDS in severe COVID-19 cases [72,73]. patients who did not receive the medicine – this difference 5.9 Interferons was not statistically significant [68]. Interferons are signalling proteins (cytokines) that alert the 5.6.2 Sarilumab body to the presence of a virus and prompt it to increase its COVID-19 is also being studied with Kevzara (sarilumab), a defences. Interferon-alpha (IFN-) and interferon-beta (IFN-) drug that operates similarly to tocilizumab. The initial results have antiviral effect against the SAR-CoV-2 virus, according were not encouraging. Patients with severe symptoms who to in vitro experiments. Interferon in combination with other received Kevzara fared worse than those who received therapy for COVID-19 has been studied in small studies, placebo, whereas patients with even more severe (critical) however the results have been varied and difficult to interpret symptoms fared better. The manufacturers are now limiting due to the low quality of the investigations [35]. their research to COVID-19 patients who are in serious 5.10 Anti-Inflammatory condition [35]. Tocilizumab and sarilumab, according to a 5.10.1 Colchicine press release from the National Health Service (NHS), Colchicine is an anti-inflammatory drug that is used to treat reduced the risk of death by 24% when given within 24 hours gout. It has a variety of effects, including activating anti- of being admitted to the ICU and shortened stays by up to 10 inflammatory mechanisms and interfering with days [69]. inflammation-causing cells. Colchicine, like tocilizumab 5.7 Anti-Parasitic (Actemra), may be beneficial in COVID-19 patients if the 5.7.1 Ivermectin immune system becomes overly stimulated and a cytokine Ivermectin is an oral medicine that is used to treat parasitic storm ensues, according to researchers. Colchicine is being infections. It can also be used to treat lice and rosacea as a tested in a big clinical trial to see if it can reduce

The J. Pharm. Sci. and Med. Res. (001) (01) (001-020) Page | 11 The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al hospitalisation and death when given shortly after a COVID- 6.0 CURRENT STATUS OF COVID 19 19 diagnosis [35]. VACCINATION In addition, a study of 105 hospitalised patients in Greece As of Jun 2021, nine different technology platforms are indicated that those who received colchicine fared better than being researched and developed to build an effective those who did not. In the hospital, one patient in the COVID19 vaccine, with the technology of several candidates colchicine group grew worse (needed ventilation or died), still unknown. The coronavirus spike protein and its compared to seven people in the non-colchicine group. Other variations are the major antigen of COVID19 infection in lab tests were carried out as well, but no differences were most vaccine candidate platforms in clinical development. found. To corroborate these conclusions, further data is Nucleic acid technologies (nucleoside-modified messenger required [35]. RNA and DNA), non-replicating viral vectors, peptides, The COLCORONA study, which has not yet been peer- recombinant proteins, live attenuated viruses, and inactivated reviewed, has also received some media attention. viruses were among the platforms being developed in 2020. Researchers discovered that non-hospitalized, high-risk Many of the COVID19 vaccine technologies being COVID-19 individuals who received colchicine had a lower researched are not like the influenza vaccines now in use, but rate of death and hospitalisation than those who did not (4.7 rather use "next-generation" tactics for precision targeting of percent vs. 5.8 percent, respectively). COVID19 infection processes. In the colchicine group, the necessity for mechanical A 2P mutation is used in several synthetic vaccines to lock ventilation was similarly reduced (0.5 percent vs. 1.0 the spike protein into its prefusion shape, which stimulates percent). These findings, however, were not statistically an immune response to the virus before it binds to a human significant, implying that they could have occurred by cell. In-development vaccine platforms may improve antigen coincidence [35]. manipulation flexibility and effectiveness in targeting 5.11 Adjunctive Treatment COVID19 infection processes in vulnerable population In critically ill COVID-19 patients, anticoagulants such as subgroups such as healthcare workers, the elderly, children, low molecular weight heparin (LMWH) are utilised to treat pregnant women, and those with weaker immune systems. disseminated intravascular coagulation (DIC) or 6.1 Vaccines based on mRNA thromboembolism [74]. Prolonged prothrombin time, When RNA is injected into a tissue, it acts as messenger activated partial thromboplastin time, increased D-dimer, and RNA (mRNA), causing the cells to produce the foreign fibrin breakdown products are all signs of thrombotic protein and stimulating an adaptive immune response that problems that necessitate anticoagulant medication [75]. teaches the body how to recognise and eliminate the LMWH works by blocking activated factor X and thrombin pathogen or cancer cells. Nucleoside-modified messenger at the same time. It also lowers IL-6 production, boosts RNA is commonly used in RNA vaccines, although not circulating lymphocytes, and improves critical-care patient always. The coformulation of mRNA into lipid nanoparticles outcomes. Patients with COVID-19 [76]. protects the RNA strands and aids their absorption into the Vitamin C is a cofactor, antioxidant, and immunomodulator cells [80,81,82,83]. that is necessary for good health. It boosts lymphocyte The first COVID-19 vaccines to be approved in the United proliferation, clears reactive oxygen species (ROS), and has Kingdom, the United States, and the European Union were antiviral properties in COVID-19 patients [77]. In severely ill RNA vaccines [84,85]. The Pfizer–BioNTech COVID-19 COVID-19 patients, intravenous vitamin C infusion reduces vaccine [86,87,88] and the Moderna COVID-19 vaccine the start of ARDS by preventing the development of cytokine [89,90] are the only authorised vaccines of this type as of storm syndrome [78]. It is also known to lower symptoms JUN 2021. CureVac's CVnCoV RNA vaccine is still pending and death in children [79], in addition to these effects in approval in the EU as of February 2021 [91]. Allergic adults. responses that are severe are uncommon. In December 2020,

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1,893,360 people received the first dose of the Pfizer– The peptide vaccine EpiVacCorona and RBD-Dimer are the BioNTech COVID19 vaccine, resulting in 175 serious two licenced vaccinations of this type as of April 2021 [113]. allergic reactions, 21 of which were anaphylaxis. Only ten The Novavax COVID-19 vaccine, SOBERANA 02 (a occurrences of anaphylaxis were recorded out of 4,041,396 conjugate vaccine), and the Sanofi–GSK vaccine are all Moderna COVID-19 vaccination dosage administrations in awaiting approval. The V451 vaccine was previously in December 2020 and January 2021. The allergic reactions clinical trials, but they were halted because it was discovered were most likely caused by lipid nanoparticles [92]. that the vaccination could potentially induce inaccurate HIV 6.2 Vaccines based on Adenovirus Vectors testing results [114,115,116]. These vaccines, which use an adenovirus shell carrying DNA 6.5 DNA Based Vaccine that encodes a SARSCoV2 protein, are non-replicating viral DNA vaccination is an alternative to traditional vaccines vector vaccines. Non-replicating virus vector-based vaccines among the technologies available for vaccine development. against COVID-19 produce only the antigen that stimulates a These vaccines, which were first discovered in the 1990s, systemic immune response rather than producing new virus have piqued the curiosity of experts all over the world due to particles [93,94]. their propensity to trigger humoral and cellular immune The Oxford–AstraZeneca COVID-19 vaccine, Convidecia, responses. A viral or bacterial gene is employed to boost the Sputnik V COVID-19 vaccine and Johnson & Johnson immune system in this form of vaccine. When a patient COVID-19 vaccine are Adenovirus Vectors based approved receives the DNA vaccine, the machinery in their cells makes vaccine till Jun 2021 [95,96,97,98,99,100]. Convidecia and a viral or bacterial protein, which the immune system detects the Johnson & Johnson COVID-19 vaccine are both one-shot as a foreign body. The immune system will then remember vaccines that require fewer logistics and may be stored for the foreign body and be able to recognise it the next time it several months under normal refrigeration [101,102,103]. enters the body, preventing sickness. The primary operating The first dose of the Sputnik V COVID-19 vaccine comprise idea of DNA vaccines is to use a DNA plasmid that encodes Ad26, which is the same as the only dose of the Johnson & for a pathogen-derived protein, in this case SARS-CoV-2. Johnson vaccine, and the second dose is Ad5. Convidecia Plasmid DNA (pDNA) is a non-viral technology that is only employs Ad5 as only dose [102]. affordable, stable, and safe, making it a viable option for 6.3 Vaccines Based on Inactivated Viruses gene delivery [117]. Inactivated vaccines are made up of viral particles that have ZyCoV-D is a DNA plasmid based COVID-19 vaccine being been produced in culture and then killed with heat or developed by Cadila Healthcare. formaldehyde to lose their ability to cause disease while still 6.6 Future Vaccine activating an immune response [104]. Nanotechnology-based vaccine development and immune- The Chinese CoronaVac, BBIBP-CorV, and WIBP-CorV; engineering techniques are particularly effective. The the Indian Covaxin; and the Russian CoviVac are based on rationale for this is that viruses and nanoparticles both act on Inactivated Virus strategy among which few vaccine are all the same length scale. The structural properties of ready approved like COVAXIN in India nanoparticles, both natural and manmade, are similar to those [105,106,107,108,109]. The Valneva COVID-19 vaccine is of viruses. Chemical biology, biotechnology, and one of the vaccines now being tested in clinical studies nanochemistry have all been used to develop next-generation [110,111]. designer vaccination technologies [14]. 6.4 Vaccines Based on Subunits 7.0 CONCLUSION Subunit vaccinations deliver one or more antigens without The present COVID-19 outbreak has triggered a global exposing the recipient to the entire pathogen [112]. Antigens health crisis as a result of its rapid spread, significant can be any molecule that is a part of the pathogen, although morbidity, and economic impact on the health sector in a they are most commonly protein components. number of nations. In order to detect COVID-19 positive

The J. Pharm. Sci. and Med. Res. (001) (01) (001-020) Page | 13 The Journal of Pharmaceutical Sciences and Medicinal Research Patel et al cases, a speedy and specific diagnostic technique is required. 7. Chibber, P., Haq, S.A., Ahmed, I., Andrabi, N.I., Singh, This would allow for immediate isolation and treatment G., Advances in the possible treatment of COVID-19: option of such patients in specialized facilities. Although A review., European Journal of Pharmacology (2020), rapid research is being conducted into the efficiency of doi: https:// doi.org/10.1016/j.ejphar.2020.173372. various medications as well as the exploration of new 8. Li, F., 2016. Structure, function, and evolution of features of the disease as potential pharmacological target coronavirus spike proteins. Annual review of virology locations, there have been no confirmed effective medicines 3, 237-261. produced to date. Currently, treatment options differ based 9. Gui, M., Song, W., Zhou, H., Xu, J., Chen, S., Xiang, on the severity of the sickness and the severity of the Y., Wang, X., 2017. Cryo-electron microscopy symptoms. Due to the considerable obstacles faced by many structures of the SARS-CoV spike glycoprotein reveal a nations in controlling COVID-19 through existing preventive prerequisite conformational state for receptor binding. measures, an efficient and cost-efficient vaccine remains the Cell research 27, 119-129. only viable option for successfully combating COVID-19. 10. Chen, Y., Liu, Q., Guo, D., 2020d. Emerging 8.0 FUNDING SOURCE coronaviruses: genome structure, replication, 688 and This research did not receive any specific grant from funding pathogenesis. Journal of medical virology 92, 418-423. agencies in the public, commercial, or not-for-profit sectors. 11. Fung, T.S., Liu, D.X., 2014. Coronavirus infection, ER 9.0 DECLARATION OF INTEREST stress, apoptosis and innate immunity. Frontiers in None microbiology 5, 296 10.0 REFERENCES 12. Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., 1. Novel Coronavirus (2019-nCoV), SITUATION Huan, Y., Yang, P., Zhang, Y., Deng, W., 2005. A REPORT - 1, 21 JANUARY 2020, crucial role of angiotensin converting enzyme 2 (ACE2) https://www.who.int/docs/default- in SARS coronavirus–induced lung injury. Nature source/coronaviruse/situation-reports/20200121-sitrep- medicine 11, 875-879. 1-2019-ncov.pdf 13. Zou, X., Chen, K., Zou, J., Han, P., Hao, J., Han, Z., 2. WHO. Infection prevention and control during health 2020. Single-cell RNA-seq data analysis on the receptor care when novel coronavirus disease (COVID-19) is ACE2 expression reveals the potential risk of different suspected or confirmedexternal icon.29 June 2020. human organs vulnerable to 2019-nCoV infection. 3. Kai-Wang To, K., Tak-Yin Tsang, O., Chik-Yan Yip, Frontiers of medicine, 1-8. C., Chan, KH., Wu, TC., Man-Chun Chan, J…Yuen, 14. Umakanthan S, Chattu VK, Ranade AV, Das D, KY. Consistent detection of 2019 novel coronavirus in Basavarajegowda A, Bukelo M. A rapid review of salivaexternal icon. Clinical Infectious Diseases. 12 recent advances in diagnosis, treatment and vaccination February 2020. ciaa149. for COVID-19. AIMS Public Health. 2021;8(1):137- 4. WHO. Transmission of SARS-CoV-2: implications for 153. Published 2021 Feb 1. infection prevention precautionsexternal icon. 9 July doi:10.3934/publichealth.2021011 2020. 15. 6 Fu L, Wang B, Yuan T, et al. Clinical characteristics 5. WHO. Clinical management of severe acute respiratory of coronavirus disease 2019 (COVID-19) in China: A infection when COVID-19 is suspectedexternal icon. 13 systematic review and meta-analysis. J Infect. March 2020. 2020;80:656–665. 6. Editor’s note, Coronavirus and COVID-19: What You 16. 7 Iyer M, Jayaramayya K, Subramaniam MD, et al. Should Know. COVID-19: an update on diagnostic and therapeutic https://www.webmd.com/lung/coronavirus approaches. BMB Rep. 2020;53:191–205.

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