A Review on Emerging Therapeutic Interventions for Corona Virus

a Department of Physiology and Biochemistry, Cholistan University of Veterinary and Animal Sciences Bahawalpur 63100, Pakistan. b Department of Biosciences, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. c Department of Pathobiology, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. d Department of Microbiology, Faculty of Veterinary and Animal Sciences, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan. e Department of Livestock and Poultry Production, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. f Department of Pathobiology, KBCMA, College of Veterinary and Animal Sciences, Narowal Campus, University of Veterinary and Animal Sciences, Lahore 51801, Pakistan. g Faculty of Veterinary and Animal Sciences, Muhammad Nawaz Sharif University of Agriculture, Multan 60800, Pakistan. h Department of Clinical Sciences, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan. i Institute of Continuing Education, University of Veterinary and Animal Sciences, Lahore 54600, Pakistan. j Department of Anatomy and Histology, Cholistan University of Veterinary & Animal Sciences, Bahawalpur 63100, Pakistan. k Department of Pharmacology & Toxicology, Cholistan University of Veterinary & Animal Sciences, Bahawalpur 63100, Pakistan. l Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore, Pakistan.


INTRODUCTION
The global challenge of COVID-19 started in late December, particular with rapid increase of critically ill patients having symptoms of pneumonia [1]. Our global health system unfortunately has often seen an array of novel emerging diseases such as Ebola, Dengue, SARS and MERS [2]. The list of emerging pathogens updated again with the addition of novel coronavirus (2019-nCoV) [3]. This virus strain was reported to infect humans for the first time [4]. In early reports the mortality rate was appears to be around 2% but with the passage of time virus became more contagious, more pathogenic and deadly. Due to globalization the virus spread across international borders and WHO declared a pandemic [5]. In corona virus illness the efficacy of the treatment totally relies on the critical condition of patient health status and disease stage [1].

SARS-CoV-2 Pathology
Coronaviridae family, having a total of thirty nine species, [6]. Few of these species are zoonotic in nature [7]. Origin and transmission patterns of the virus, still remain as unidentified to world audience, recently, it is believed that SARS-CoV-2 has been transmitted to human being from mysterious animal and further transmitted from one individual to another [8]. Coronaviruses affecting human being are causative of upper respiratory tract diseases limiting from minor to moderate symptoms together with common cold [9]. Human might be infected with more than one species of this coronaviridae family at any stage during their life span [10]. Two main etiological agents of severe pneumonia are MERS-CoV and SARS-CoV [11]. There are sight variations among the signs and symptoms of MERS, SARS, COVID-19 and common. The World Health Organization publically named this viral disease COVID-19 on 11, February 2020 [12]. This new virus was termed as SARS-CoV-2 by the research group of the International Committee on Taxonomy of Viruses [6]. In arrays of serious outbreaks SARS-CoV first appeared in 2002. 8000 infections and 774 deaths were recorded across 35 countries during its course of infection [13]. Followed by the outbreak of MERS-CoV, responsible for infection of 2500 people and 858 dead in golf states [14]. Similarly, the newly emerged SARS-CoV-2 transmitted from animals to human beings in December 2019. Currently 34,170,356 people are infected and reported deaths are 1,018,899 worldwide. Incubation period of SARS-CoV-2 is about 14 days. It replicates in the lower and upper part of respiratory tract as a result produced lesions in the affected areas [15]. Most common clinical signs and symptoms found are cough, low to high grade fever, dyspnea and lesions in lungs [16]. There may be development of pneumonia in the later stages that leads to (ARDS) acute respiratory distress syndrome and severe pneumonia which follows into life-support to save the life of infected individual [17]. Generally, the HCoVs are long single-stranded positive-sense RNA viruses (30,000 bp). HCoVs characterize by two groups of proteins; non-structural proteins and the structural proteins as RNA dependent RNA polymerase (RdRp) (nsp12) [18]. Research studies show that convalescent plasma obtained from patients who have cured from viral diseases may be used as a treatment without the incidence of severe contrary effects. Therefore, it could be valuable to test the efficacy and safety of convalescent plasma transfusion in SARS-CoV-2-infected patients. Li et al., [31] described the medical characteristics & cytokine structural profile of serious patients in Wuhan, China with COVID-19 and recommended that a cytokine storm (i.e. interferon gamma-induced protein 10, higher concentrations of granulocytecolony exciting factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1α and tumor necrosis factor α) might be related with the severity of disease [32]. Another research report from China described that improved expression of interleukin (IL-6 & IL-2R) in serum acts to anticipate the severity and prognosis of patients with SARS-CoV-2. Furthermore, histopathological analysis of a biopsy section obtained from an expired person infected with COVID-19 showed that interstitial mononuclear inflammatory infiltrates dominated by lymphocytes, in right and left lungs [32]. Additionally, et al., [33] reported that marginal blood flow cytometric analysis revealed that the over activation of T cells accounted for the serious immune damage in the diseased person. Therefore, the cytokine storms would never be ignored in the treatment of novel COVID-19. Immunomodulatory therapy to down-regulate the cytokine storm can facilitate the insights in COVID-19 treatment [32]. In immunomodulatory therapy of infectious diseases, corticosteroids are among the most normally used medicines. However, in the treatment of COVID-19 the use of corticosteroids can cause host immune suppression and postponed viral clearance. Recently Liu et al., [34] reported that chloroquine and its derivative like hydroxychloroquine have been found effective in the cure of SARS-CoV-2. In China in February, 2020, outcomes from more than hundred COVID-19 infected patients revealed that chloroquine phosphate had better effectiveness against the virus. Additionally, their anti-inflammatory properties, antiviral and antimalarial effects have already been confirmed in the therapy of autoimmune diseases like lupus erythematosus and rheumatoid arthritis. Hydroxychloroquine and chloroquine can prevent the main histocompatibility complex class II expression, immune stimulation (reducing CD154 expression by T cells) and antigen appearance through cGAS activation of interferon genes and Toll-like receptor signaling [35]. Thus, hydroxychloroquine and chloroquine can decrease the growth of numerous proinflammatory cytokines, such as interferon-α, IL-6, IL-1 and tumor necrosis factor associated in the cytokine storm.

Therapeutic
The virus completes its cycle in the five stages as; attachment, penetration, biosynthesis, maturation and release. The COVID-19 virus binds with its spine proteins (S protein) to the angiotensin exchanging enzyme-2 receptor (ACE2), [29] whose expression levels are higher in lungs, heart, ileum, kidneys and bladder could explain the involvement of multiorgan failure in COVID-19 patients . Moreover, type II alveolar cells are also the precursors of type I cells, hence after their destruction, the regeneration mechanism of alveolar units is severely impaired [40]. Much of the damaged inflicted by SARS-CoV-2 is presumably due to a robust immune reaction called cytokine storm with IL-6 as a major protagonist. This IL-6 is also a major culprit implicated in production of acute phase proteins, thermoregulation fever and multiple organ dysfunction.
Moreover, inhibition of ACE2 receptor by the virus further promotes lung injury as occupied ACE2 receptors fail to breakdown angiotensin II that leads to severe respiratory distress syndrome & multiorgan dysfunction [41]. These events cause diffuse alveolar injury with fibrin rich hyaline membranes and a few multinucleated giant cells. In terminal stages of COVID-19 patients, consumption of clotting factors and stimulation of coagulation occur with resultant diffused intravascular coagulation [42]. Swollen lung parenchyma and pulmonary endothelial cells may cause the thrombi formation. Viral sepsis is considered as among the important complications that are associated with COVID-19 is caused by dysregulated reaction of host defense system and this sepsis could also play its part in multiorgan failure [37].

Specific strategies to combat
The choice of whether to admit a patient in the hospital or not depends on the extent of progression of virus in the respiratory tract [43].
The patients in which the COVID-19 has just spread to upper and conducting part of respiratory airways exhibit mild symptoms, such as fever, cough and do not need immediate hospitalization. Instead they need to be isolated at home to reduce and mitigate the transmission of infection and such house-quarantined patients should receive much of their treatment at home including spirometry or breathing exercises, rest, and adequate fluid intake and antipyretics. It is only in severe case in which the virus has acquired access to gas exchange area of the respiratory airways and other parts of the body where the situation gets complicated with sepsis, severe respiratory distress syndrome, multiorgan failure and septic shock including cardiac and renal failure [44], that the patient should be admitted to the hospital and be treated according to the complications involved. The severity of the disease is assessed by the development to of ARDS which is a syndrome described by sudden commencement of hypoxemic respiratory failure along with bilateral infiltrates [45]. The COVID-19 patients who suffer from other comorbid conditions such as diabetes and cardiac diseases also require immediate medical intervention as the chances of complication are elevated in these patients [46]. The most common condition for requiring extensive care has been respiratory support. Therefore, those patients who develop respiratory distress, hypoxia or shock should immediately be given supplemental oxygen therapy and their SpO2 should be tried to maintain at >94% [47]. If the patients continue to develop hypoxemia even after oxygen therapy should be opted to treat with mechanical ventilation with prone ventilation of 12-16 hours is recommended [48]. Similarly, those individuals who suffer from co-infections should be empirically treated with antimicrobial within an hour of their assessment.

Availability of Targeted Drugs
Ivermectin is a potential drug of choice against parasites and it is also proposed for treatment against SARS-CoV-2 [49]. The concentration at 5 mmol/L causes the disappearance of RNA of virus and it is 50 times over higher after 700 lg/kg attained [50]. Ivermectin showed a great anti-viral activity (broad spectrum) in vitro and it prevents COVID-19 with addition Vero-hSLAM cells. Its affects showed activity 2 hours after post infection and reduced the viral RNA ~5000-fold in 48 hours.
A nucleoside analogues drug, Remdesivir has antiviral activety and used for treatment of infections caused by Nipah and Ebola virus [51]. Remdesivir has greater effects on SARS-CoV-2 as it is an RNA virus and has great potential candidate drug for the therapy of COVID-19 [52]. The mode of action of Remdesivir which targets the divergent RNA-dependent RNA polymerase (RdRp) of host viral replication and its nucleoside analogues shows the antiviral results as in HIV, hepatitis C and B. it is used with ribavirin and mutation was increased by 9.7-fold reduce infection at 99.3% [53]. Azidothymidine loses its 3′-hydroxyl group which is necessary for synthesis of additional DNA. Remdesivir blocks the transcription process at 3′-hydroxyl and produced phosphodiester bond with nucleotide. Patient infected with COVID-19 received Remdesivir 200 mg I/V in 1 day up to 10 days. So, 61 patients recovered successfully as they belong from different countries as Europe, United States, Canada and Japan.
Favipiravir inhibited the RNA-dependent RNA polymerase (RdRp) (Dong, 2020) and block the replication of alpha-, flavi-, bunya-, filo-, noro-, arena-, and other RNA viruses [54]. Many clinical trials are undergoing for the use of treatment of COVID-19. 120 patients of COVID-19 treated with Favipiravir and compared Arbidol. Recovery rate is day 7 and recovery rate was 0.0954; 95%. Serum uric acid was raised by using of Favipiravir and it helps to relief from cough and pyrexia and adverse effects can be manageable.
MK-4482 is an emerging drug which has antiviral potential, so it can be used for treatment of COVID-19 [55]. A new route has been developed for MK-4482 from cytidine which is desirable for many reasons. It emits O-acylation which is undesirable and less chemical esterification plan. Further trails are necessary to check its effectiveness for the treatment of COVID-19. MK-4482 shows more better results than that of remdesivir for the treatment of patients infected with COVID-19 and its trials have been conducted in mice [56].

CONCLUSION
The COVID-19 pandemic is an ongoing problem that disturbs the normal living of most of the people all over the world. Many countries of the world are now closed or semi-closed, strict transportation and travel regulations have been passed, international dealings have been suffered seriously and humans are exposed to an exceptional regime, which has changed the normal phenomenon of life. Immune system plays a significant role in combating COVID-19, unexpectedly it could also be dangerous. Now a day's target drugs are available and due to limitation of choice being catagories as best treatment for corona virus. It is compulsory to find effective drugs and vaccines to return towards the normal situation and reduce the mortality rate.

CONSENT
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ETHICAL APPROVAL
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