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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 2  |  Page : 110-120

A review on Coronavirus Disease and potentially active drugs targeting Coronavirus


1 Department of Chemistry, I.K. Gujral Punjab Technical University, Jalandhar, India
2 Department of Chemistry, Laureate Institute of Pharmacy, Kangra, Himachal Pradesh, India
3 Department of Pharmaceutical Sciences, Ch. Bansi Lal University, Bhiwani, India
4 Department of Chemistry, S.P. Jain College, Veer Kunwar Singh University, Sasaram, Bihar, India
5 Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
6 Department of Ayush, Drugs Testing Laboratory Avam Anusandhan Kendra, Raipur, Chhattisgarh, India

Date of Submission03-Feb-2021
Date of Acceptance21-Mar-2021
Date of Web Publication16-Jun-2021

Correspondence Address:
Dr. Kamal Shah
Institute of Pharmaceutical Research, GLA University, Mathura - 281 406, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_14_21

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  Abstract 


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus with single positive-strand RNA, having glycoproteins projection on envelopes so reveals a halo-like appearance or corona. Coronavirus is of four types: (1) α-coronavirus (α-COV); (2) β-coronavirus (β-COV); (3) δ-coronavirus (δ-COV); and (4) γ-coronavirus (γ-COV) and belongs to family Coronaviridae and subfamily Coronavirinae. Coronaviruses are the normal pathogens that cause broad band of gastrointestinal and respiratory diseases in domestic as well as wild animals such as pigs, birds, and rodents. Coronavirus is highly infectious in case of elders for mortality rate. The elder peoples are at 2-fold higher risk as compared to the younger population and the greater part of the population dying from coronavirus disease (COVID-19) is male. The virus enters into the body by the mouth, eyes, or nose, then particles march inside of the body by different pathways and affect vital organs in severe ways such as liver, heart muscle, blood vessels, kidneys, central nervous system, etc. Right now, the only solution to avoid COVID-19 infection is “precautions.” Different companies of different countries at different steps are in race to develop effective medicines for treatment and management of the same. Here, in this review, we tried to give an overview of all about SARS-CoV-2, COVID-19 infection, pathophysiology, mechanisms, and various treatment trials.

Keywords: ACE2 receptors, antivirals, coronavirus, coronavirus disease, cytokine storm, remdesivir, severe acute respiratory syndrome coronavirus 2


How to cite this article:
Verma T, Sinha M, Nitin B, Yadav SR, Shah K, Chauhan NS. A review on Coronavirus Disease and potentially active drugs targeting Coronavirus. Biomed Biotechnol Res J 2021;5:110-20

How to cite this URL:
Verma T, Sinha M, Nitin B, Yadav SR, Shah K, Chauhan NS. A review on Coronavirus Disease and potentially active drugs targeting Coronavirus. Biomed Biotechnol Res J [serial online] 2021 [cited 2021 Aug 2];5:110-20. Available from: https://www.bmbtrj.org/text.asp?2021/5/2/110/318422




  Introduction Top


Coronavirus says, “If you want to go with me then don't maintain physical distance, don't hygiene your hands, don't follow cough etiquettes and don't wear a medical mask.”

In late December 2019, a group of patients who suffered from pneumonia suddenly of unknown reason was having common thing that the whole group was linked to a wet animal and seafood wholesale market, which deals in wild animals also, in Central China's Hubei province Wuhan. Later on, the causative pathogen was identified as a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease (COVID-19).[1] Later, it was named as 2019-nCoV where “n” situated for novel which was responsible for severe acute respiratory problems as well as fever, abdominal symptoms, weakness, shortness of breath, and pneumonia.[2],[3]

Later on, it was confirmed that 2019-nCoV transmitted in humans through human interactions, large droplets and fomites, and in Wuhan, in other foremost cities of China as well as many countries of the world by travelers upcoming from the affected countries with reported cases[4] the COVID-19 infections rose rapidly. In last of May 2020, Kimberly Prather proved that COVID-19 causing particles (aerosols) are too small to float freely in the air. The size of aerosols is in microns; they can float easily in the air (around 6 feet) for a long time and take hours to settle down [Figure 1]. These aerosols can easily be inhaled inside the lungs deeply.[5] The WHO and different governments have been made a number of action plans to control the plague of the virus. Right now, the efficient medical methods are in significant requirements to avert the 2019-nCoV infection outbreak and treat it.[2]
Figure 1: Structure of coronavirus

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SARS-CoV-2 is a virus with single positive-strand RNA, having glycoproteins projection on envelopes so reveals a halo-like appearance or corona. Coronavirus is of four types: (1) α-coronavirus (α-COV); (2) β-coronavirus (β-COV); (3) δ-coronavirus (δ-COV); and (4) γ-coronavirus (γ-COV) and belongs to family Coronaviridae and subfamily Coronavirinae. Coronaviruses are the normal pathogens that cause broad band of gastrointestinal and respiratory diseases in domestic as well as wild animals such as pigs, birds, and rodents. from the coronavirus family; till date, seven members are find out, three out of them belong to among the coronavirus family, seven viruses are known, out of them three belong to β CoV (SARS CoV 2, SARS CoV, Middle East respiratory syndrome CoV). They are responsible for cluster of severe acute infection mainly respiratory tract infections in human beings[6] [Table 1]. The remaining four coronavirus strains circulating yearly cause casual pathogenic infection such as common cold.[8],[9],[10],[11]
Table 1: Characteristics of different coronavirus strains

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At present, the infection of COVID-19 has been spread to more the 108 countries around the world.[3] The patients of COVID-19 increased 10 folds in the last 1 month as the number of cases was 100,000 in starting of March, now reached to one million in starting of April. On January 31, 2020, the World Health Organization (WHO) declared that COVID-19 was scheduled as the Public Health Emergency of International Concern, meaning that it may pretense threat to several countries and need a harmonized international response.[12] Right now, the COVID-19 positive patients have been found in most of the countries about the world.[13],[14] At time of this review, world has 14,746,153 confirmed case with 610,784 deaths and 8,800,516 recovered patients (CDC, WHO).[15]


  Age and Coronavirus Disease Top


Some studies reported that coronavirus is highly infectious in case of elders for mortality rate as well as no of cases. The elder peoples are at 2-fold higher risk as compared to the younger population. Further, the areas or countries, where the population of elders is more than younger, are reporting a higher proportion of confirmed cases of COVID-19. The elder patients having rheumatic and musculoskeletal diseases health problems are at 5 times higher risk then younger patients.[16],[17]


  Sex and Coronavirus Disease Top


A universal quote, that COVID-19 does not distinguish, is wrong. There are many factors race, dimensions of class, previous health condition, particular geographical area, gender, etc., allow people to more susceptible, worldwide, in favor of the entire age group. In case of gender gap, i.e., male social worker death rate from COVID-19 is 23.4 deaths per 100,000 and the female social worker death rate is 9.6 deaths per 100,000 in England and Wales. In different countries as data available, it is not clear that whether men or women are more expected to be analyzed with COVID-19. In some countries, confirmed cases of women are over 50%, but in other cases, confirmed cases of men are higher than 50% [Figure 1]. But obtained data showed that the greater part of the population dying from COVID-19 is male [Figure 2] and [Figure 3].[18],[19]
Figure 2: Coronavirus disease cases of % male and % female on July 16, 2020

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Figure 3: Coronavirus disease death rate of % male and % female on July 16, 2020

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  Pathogenesis of Severe Acute Respiratory Syndrome Coronavirus 2 Top


Severe acute respiratory syndrome coronavirus 2 fusion with cell

According to the literature survey microscopically, SARS-CoV-2 binds to ACE-2 receptor to enter into the host cell and employs Transmembrane Serine Protease 2 and furin, the host cell enzyme, for spine protein priming.[20],[21] After priming, the virus enters into the cell by fusion with peptides present on the host cell membrane.

Entry and replication

Coronaviruses are acellular and their replication is depending upon cell machinery. The virus life cycle completes in six stages as shown in [Figure 4]. First of all, the virus attaches with the host cell by the specific receptor present on the membrane of the host cell. After attachment, the virus penetrates into the cytoplasm of the host cell by the cell membrane. In the cytoplasm, genetic material gets released from the protein coat of the virus by uncoating. So, after uncoating, the RNA gets released into the cytoplasm. Where, by reverse transcription, viral RNA converts into the viral DNA in the presence of reverse transcriptase enzyme. The viral DNA gets integrated with the host DNA into the nucleus with the help of enzyme integrase. Integrated DNA produces viral genomic RNA and by transcription, integrated DNA forms viral mRNA which undergoes translation to form viral protein. Through packaging and assembling, viral genomic RNA gets inserted into the viral protein. Now, it is a complete virus particle and gets released as a mature virus by budding with the help of the neuraminidase enzyme. Now, this mature virus can infect any other living cell.[19],[20]
Figure 4: Pathogenesis of virus in host

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  Symptoms of Coronavirus Disease Positive Patients Top


The virus particles enter into the cell by binding on target receptor (ACE2 receptors). The ACE2 receptors are present on the surface of the cell in almost every organ of the body. So, they are available in large abundant for the virus to bind. Once virus particles enter into the nose, eyes, or mouth, the virus connects to the ACE2 receptor of the host cell by “spike proteins.” The host cell machinery sponsors replication of the virus to produce millions of copies which convert it into a production factory. The product of this factory spreads outside by coughing, sneezing, and breathing.[22],[23],[24] At the time of infection, host cell cannot call for help as the coronavirus suppresses the host cell in multiple way, i.e., it trims distress signal proteins and inhibits the cell to give the signal of under attack. As it controls host cell machinery almost completely, it obliterates antiviral commands within the infected cell. In this way, the virus got more time to multiply and invade surrounding areas before identify and activation of immune responses. The infected person's strong immune system can defend against the virus at a stage earlier than it gets worse. But if it could not happen at an early point, these particles march inside of the body by different pathways like either by making camps inside the lungs or by struggling with the immune system in the digestive tract or by combination of both. Because of these ways, patients having respiratory syndrome and gastrointestinal illnesses like diarrhea associated with abdominal pain or both.[25]

Direct attack

Early reports of biopsy and autopsy show that particles of the virus also present in the heart, kidneys, pancreas, liver, brain fluid, stool, and tears. As ACE2 receptors are present at every organ of the body after deep invading virus further affects the liver, heart muscle, blood vessels, kidneys, central nervous system, etc., in severe ways.


  Management Top


There are a lot many drugs used during the management of this viral infection. Few are discussed here with category and their examples. For examples Immunomodulators (Chloroquine and Hydroxychloroquine), Broad-spectrum anti-viral (acyclovir), Protease inhibitors (ritonavir) RNA-dependent RNA polymerase inhibitor (Remdesivir), Anti-fusion (Arbidol), Corticosteroids (Betamethason), Cytokine directed therapy (Recombinant IFN),

Anti-IL-6R (Tocilizumab), Cyclophosphamide (Rituximab), Neutralising Antibodies and Convalescent Plasma Therapy, etc.[26],[27],[28],[29],[30],[31],[32],[33],[34]

Fusion inhibitors (enfuvirtide) inhibit fusion of virus with the host cell, amantadine/rimantadine inhibiting uncoating of the virus into the cytoplasm. Reverse transcriptase inhibitors (zidovudine/didanosine) inhibit reverse transcription by blocking the action of reverse transcriptase. Integrase inhibitor (raltegravir/dolutegravir) block integrase enzyme and inhibit the integration of viral DNA with host DNA. Protease inhibitors (indinavir/nelfinavir/ritonavir) inhibit viral protein synthesis and block the formation of multiple copies of the virus. Neuraminidase inhibitors (zanamivir/oseltamivir) block neuraminidase enzymes and inhibit the release of mature virus [Figure 5].[35]
Figure 5: Mechanism of actions of viral drugs

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Collateral injure that kills

The virus causes severe damage to the lungs which triggers the activation and overstimulation of the immune system by the bombardment of cytokines, a signaling chemical. This “cytokine storm” causes an emergency situation in which blood pressure get decreased, cytokines magnetize more killer immunity cells and inflammatory cells, and direct to even additional injury in the heart, lungs, brain, and kidneys. Some researchers explain that this cytokine storm is responsible for sudden decompensation which leads critical illness in corona virus-positive patients. In a recent finding according to many doctors, abnormal clotting or thrombosis may be one more lethal culprit for the critical condition of COVID-19. According to observations of doctors, clots are present all over the body, for example, in large vessels and small blood vessels of multiple organs, at a higher rate than normal thrombosis even the patients are on clot prevention therapy by blood thinner. According to a dermatologist Sanober Amin, Texas, blood clotting is also observed in superficial blood vessels next to the skin called as “COVID toes/Pernio” in COVID-19 positive people. Although the reasons of this type of clotting are not clear yet, it seems a measure cause of death in patients. further than the collateral injures from clotting and cytokine storms, other conditions like decrease blood pressure due to severe illness, drug treatments with different drugs, oxygen supply on the ventilator at low levels of oxygen, etc., themselves collectively can harm body organs throughout, together with the liver, kidneys, heart, brain, etc., [Figure 6].
Figure 6: Pathogenesis of coronavirus disease/severe acute respiratory syndrome coronavirus 2. Where ROS: Reactive oxygen species; ALI: Acute lung injury; ARDS: Acute respiratory distress syndrome

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Double-edged sword

The research and studies made the doctors to know at daily bases that the main points of problem are ACE2 receptors, cytokine storms, and clotting. The question in mind that these points may be targets of treatment. But this is again not as easy as the targeting drugs can destroy the delicate balance that helps to fight against disease and manage inflammation naturally.

ACE2 receptors which are used by the virus to enter in the cell are playing a key role in blood pressure lowering and managing inflammation. Targeting or masking these receptors as a healing approach to inhibit virus to enter into host cell may worse blood pressure which actually enhance heart and kidney failure risks. It may also deteriorate lung damage by increasing inflammation.

The cytokine storm occurs due to the immune response of the body which is required to fight against the virus or other diseases for a long run. Masking or targeting immune response creates a harder situation for the body to fight against virus naturally over a long time. Furthermore, blood thinners or blood clotting inhibitor/anticoagulation drugs may lead to severe bleeding as limited or zero evidence on bleeding threat. Actually, it is a two-edged sword situation. Doctors also suggested that patients require immune system booster to fight against disease at an early stage and if virus progresses, further leads to a cytokine storm that can be mask with drugs.

Just the tip of the iceberg

According to researchers and doctors, ACE2 receptor, cytokine storm, and high rate clotting all the reasons are known, and treatment strategies also present, but in case of COVID-19, all the approaches “is just the tip of the iceberg.” Researchers are still required to work hard patiently to find out the ways.

Unanswered questions

Till date, much information is present about COVID-19 symptoms from patients who are hospitalized seek care and other who are not able to share information. Observers and doctors up till now do not even know the full level of description of infection from mild and moderate or effects of infection on patients who are not quite sick to hospitalize with many symptoms. Beyond the treatment and survival, there are some other questions also that are not answered till date:

  1. What will be the long-term effects on COVID-19 positive survivors?
  2. How the lives look like following a sudden ventilator or dialysis?
  3. Will the decreased lung, heart, and kidney permanent/long lasting or patient finally recovered?
  4. How patients will clear coronavirus infections?


Possibilities are, may be COVID-19 ends up as an acute infection with a developed short-term immunity in most recovered persons. The virus may also continue as a dormant illness, as chickenpox, lying inactive in the body, or as an unceasing infection, such as hepatitis B, alive in body cause long period damage for continual time episode.[36],[37],[38],[39]

Ravulizumab-cwvz (ULTOMIRIS) is the first C5 complement inhibitor at the endpoint of the complement cascade. The 5th complement component is a protein which plays a vital role in cell killing and inflammatory processes. This is made up of alpha and beta polypeptide chains which are linked by a disulfide bridge. By action of C5-convertase, C5α gets cleaves and causes potent chemotactic and spasmogenic activities. When C5α component is activated at an uncontrolled level, leads to over-respond of the complement cascade, followed by attaching of the body's immune system on healthy cells.[40] In the lungs of rigorously ill COVID-19 patients, interleukin-33 (IL-33) is involved in motivating and intensifying the overactive inflammatory reaction that damages the lungs, liver, and other vital organs. In ACCORD trials, it will review that whether these IL-33 can lessen the cytokine storm by a viral infection or not.[41],[42],[43] Soliris can help to reduce organ damage in critical patients by crashing the complement system.[44],[45],[46] Infliximab (CT-P13) is an antitumor necrosis factor, right now, it is in the market as Remsima® (trade name) for treatment of inflammatory conditions with eight other autoimmune diseases like bowel syndrome and rheumatoid arthritis, etc.[47],[48],[49],[50] Emetine acts by inhibiting ribosomal protein synthesis and block viral-RNA synthesis.[51] Sialic acid is used by different viruses as entry receptor for infection in epithelial cells. A recombinant sialidase protein (DAS181) can cleave this sialic acid and inhibit binding, entry in epithelium cell, and respiratory system infection by virus.[52],[53],[54] Kaletra acts by inhibiting Cytochrome P450 enzyme and already permitted for treatment of HIV. In case of coronavirus, it can inhibit the synthesis of necessary proteins which are required for the life cycle of the virus.[29],[55],[56],[57],[58],[59],[60],[61] AT-527 is an orally active antiviral pro-drug which can inhibit enzyme RNA polymerase including coronavirus.[62],[63] Ribavirin (Virazole) inhibits virus replication. This drug is contraindicated in pregnant females and it is teratogenic effect in animals.[64],[65],[66] Favipiravir arrests replication of virus by inhibiting RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2.[67],[68],[69],[70],[71],[72],[73],[74] Remdesivir is a competitive inhibitor of RNA-dependent RNA polymerase.[75],[76],[77] PREZCOBIX is protease inhibitor drugs.[78],[79],[80],[81] Arabidol, an indole analog, can inhibit the fusion of host cell membrane and virus lipid shell and penetration of the virus into the host cell.[82],[83] Neurosivir is a competitive inhibitor of RNA-dependent RNA polymerase.[68],[69],[70],[71],[72],[73],[74],[75],[76],[77] Truvada is a reverse transcriptase enzyme inhibitor.[84],[85],[86] EIDD-2801 acts by inhibiting the reproduction of multiple RNA viruses[87],[88],[89] [Table 2].
Table 2: Drugs in different phases of clinical trials for COVID-19

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A hyperimmune globulin drug, GC5131 is prepared by different efficient immune antibodies taken from the same fully recovered patients.[90],[91] Emapalumab (Gamifant) can bind and inactivate interferon gamma.[92],[93],[94] Gimsilumab acts by targeting granulocyte macrophage-colony stimulating factor is a growth factor.[95],[96],[97] REGN-COV2 binds noncompetitively to spike protein of SARS-CoV-2 on receptor binding domain.[98],[99] Actemra/RoActemra acts on chimeric antigen receptor on T-cell and used to treat life-threatening or severe cytokine release syndrome[100],[101],[102] [Figure 7] and [Figure 8].
Figure 7: Mechanism of action of different anticoronavirus disease drugs under clinical trials

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Figure 8: Mechanism of action of different anticoronavirus disease drugs under clinical trials

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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