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Review Article

Assessment of Interference Approaches in Response to COVID-19 Outbreak

Khurshied AK1*, Junwei L2, Murtaza H3, Ikram ul HM1, Jamal MK4, Zahoor M5, Osama G6, Muhammad HS7, Hameed MS1, Khaliq MA1, Shahbaz A1, Ahmed KK1, Tahria BQ1, Maqbool A1, Nisar H1, Matlob A1, Ijaz Hussain M1 and Asma N1

1Ghazi University City Campus, Dera Ghazi Khan 32200, Pakistan

2Department of Infectious Diseases, The Second Hospital of Nanjing, The Affiliated Hospital of Nanjing University of

Chinese Medicine, Nanjing, 210003, China. Public Health and Therapy Center of Nanjing, Nanjing, 211113, China

3Department of Biochemistry and Biotechnology The Islamia University Bahawalpur 63100, Pakistan.

4Cholistan University of Veterinary and Animal Sciences, Pakistan

5China Agriculture University Beijing

6Nowshera Medical College, (KMU) Nowshera, Pakistan

7Iqra University Islamabad Pakistan

Received Date: 18/05/2020; Published Date: 23/06/2020

*Corresponding author: Khurshied Ahmed Khan, Ghazi University City Campus, Dera Ghazi Khan 32200, Pakistan. E-mail: kakhan@gudgk.edu.pk

DOI: 10.46998/IJCMCR.2020.01.000013

Abstract

The start of (2020) is underway with the rise of novel coronavirus known as SARS –CoV-2 that triggering pneumonia-related respiratory syndrome all over the world. It is the third intensive pathogenic and contagious coronavirus after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) appeared in humans. The cause of beginning, diffusion to humans and contrivances linked with the pathogenicity of SARS-CoV-2 are not vibrant yet, however, its similarity with SARS-CoV and numerous other bat coronaviruses was newly established and concluded through genome sequencing interrelated studies. The progress of therapeutic strategies is required in order to inhibit further epidemics and cure disease-ridden people. In this Review, we summarize existing data about the development, source, diversity, and epidemiology of three pathogenic coronaviruses with a detailed attention on the present outburst in Wuhan, China. Additionally, we discuss the clinical features and potential therapeutic possibilities that may be effective counter to SARS CoV-2.

Keywords: Novel coronavirus; Outbreak; Therapeutics

Introduction

The episode of coronavirus infection 2019 (COVID-19) gears in Wuhan city, Hubei province of China initially developed in December 2019. Recently known unique coronavirus (SARS-CoV- 2, earlier known as 2019-nCoV) is affecting pneumonia related respiratory syndrome [1]. Subsequently investigation of genome classifications of SARS-CoV-2 samples collected from various disease-ridden patients, SARS-CoV-2 bonds strong sequence uniqueness with SARS- CoV [2]. At mid of April 2020, about 209 countries reported >1.9 million cases of SARSCoV-2 infection. Patients diseased with SARS-CoV-2 showed confirmation of common pneumonia with serious lung damage [3]. COVID-19 could be distinguished by clinical CT radiography or a laboratory real time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) [4].

Unluckily, there is no particular antiviral drug or vaccine now a days. Some options can be used to switch infections of SARS-CoV-2, including vaccines, antibodies, inhibitory mechanism and small molecules drugs [5]. The antibody reaction is a key for averting viral infections. A subclass of these antibodies, which condense viral infection by adhesion to the epitopic area of viral fragments and thereby hindering the access of the virus to an infected cell, are defined as negating antibodies (NAbs) [6]. This review concentrates on understanding immuno- pathogenesis of SARS-CoV-2 and discussing the advances, challenges and studies of neutralizing antibodies (NAbs).

Diversity and Source of Extremely Pathogenic Coronaviruses

Diverse strains of MERS -CoV reported from camels were establish parallel to those isolated from humans [7], excluding, genomic dissimilarities among S, ORF4b and ORF3 regions [8]. Moreover, genome sequencing -established studies exposed that MERS -CoV s from humans are phylogenetically correlated to those form bats. They have undistinguishable genomic and protein assemblies excepting for the S proteins [9]. In addition recombination s analysis of genes encoding orf1ab and S shown that MERS -CoV patented from the give-and-take of genetic components between coronaviruses in camels and bats (10). While the zoonotic origion of SARS

-CoV-2 is not proved, its genome sequence revealed adjacent affinity (88% identity) with two bat -resultant SARS -like coronaviruses (bat - 89 SL -CoVZC45 and bat -SL-CoVZXC21). Phylogenetic examination discovered that SARS -CoV-2 was genetically distinctive from SARS

-CoV and MERS -CoV. However, homology exhibiting shown that both SARS -CoV and SARS

-CoV-2 had analogous receptor-binding sphere structures, despite amino acid disparity at some crucial remains. Such as the absence of 8a-proteinand non-stable number of amino acids in 8b and 3c-proteins in SARS -CoV2. In contrast, the core protease is extremely well-maintained among SARS -CoV-2 and SARS -CoV with a 96% complete uniqueness. These remarks advocate that bats are the foundation of source, whereas an animal retailed in the Wuhan seafood market strengthen a transitional cloud aiding the beginning of the virus in humans [10].

Clinical features connected with patients affected with SARS -CoV, MERS -CoV and SARS - CoV-2 ranging from a slight respirational epidemic to serious critical respiratory illness. Both MERS and SARS patients in later phases mature respiratory suffering and renal letdown. Pneumonia appears to be the record and repeated index of SARS -CoV-2 infection, considered mainly by fever, cough, dyspnea, and related infiltrates on chest imaging. The period from infection to appearance of symptoms differs. Commonly, it is supposed to be 14 days, but, a study group at Guangzhou Medical University stated the maturation period to be 24 days. In a local cluster of groups and joint families the infections start of fever and respiratory illness signs transpired about three to six days after possible contact [11].

Therapeutic Possibilities for Human Coronaviruses

Presently no favorable antiviral cure existing, however, frequent compounds have been established active against SARS -CoV and MERS -CoV but not verified extensively for recently appeared SARS -CoV – 2.

Development of Neutralizing Antibodies to 2019-Ncov

Coronavirus access rises with the S protein binding to a destination receptor on the cell surface, where after merging is facilitated at the cell membrane, providing the viral nucleocapsid into the cell for consecutive duplication [12]. The S protein is well-known for triggering syncytial development into diseased cells and receptor-contaimimg cells around them, highlighting that the S proteins are not only functional inthe virion state.

A neutralizing antibody aiming the S protein on the surface of 2019-nCoV is possibly the first therapy expected by biomedical investigators in academics and industry, serve as an inert protection to illness [13].  The newly available genome sequence of   2019-nCoV (GenBank: MN908947.3) permits scientists to triumph gene fusion in the lab and reflect stating the S protein as an immunogen. Conventional approaches of screening mice or rabbits for neutralizing antibodies may be quite paasive for this outbreak, but quick methods such as, super computer that express antibody fragments could be used to classify prime competitor for viral neutralization [14].

The problem is that some antibody aspirant would be carefully deep-rooted in cell culture and animal models to endorse that it can neutralize 2019-nCoV and avert epidemic. Evidence from other coronaviruses types such as SARS could be supportive to target the best epitope in order to create neutralizing antibodies (the receptor-binding area in the S protein is a significant target) [15], but again this is a time cosuming and thought-provoking procedure, which might not return substantial advances for some months. Furthermore, finally a combination of antibodies might be vital to safeguard full defense for long suffering patients, which could enhance supplementary complication for preparation and production.

A substitute approach of creating counterbalancing antibodies contrary to 2019-nCoV S protein could develop immunity in large animals (sheep, goat, and cow) with the 2019-nCoV S protein, and then liberating and cleaning the polyclonal antibodies from the animals [16].This approach may assist an accelerated facility in the background of an epidemic and has several leads such as  streamlining assembly and built-up, but has partial assurances that every animal could create neutralizing antisera, or the antibody titer present in each animal [17]. In addition, the human immune reaction’s counter to foreign immuno-globulins to other species, which could hypothetically confuse any cure developments [18]. In a really anxious situation, this approach may be practical for a precise range, but not balanced in the 2019-nCoV epidemic, that is promptly proliferating currently [19].

Perceptions on the Progress of Neutralizing Antibodies against SARS-Cov-2

To practice the Plasma transfusion of recovered patients in the infected patients would be an alternative approach during the outbreak, due to presence of Polyclonal Nabs. [20]. These Polyclonal NAbs could be active and effective in in handling SARS-CoV-2 if induced properly [21]. Further these NAbs can deal with inactive immune responses to viral infection in the patients. Actually Convalescent plasma therapy was successfully applied to SARS and Ebola infected patients in past and established and marked as curing therapy but the problem and challenges during this therapy are irregularity inert plasma and inconsistency of sera in different patients [23]. To make the therapeutic antibodies successful antibody-antigen computational model can developed to monitor the strategy [24]. The Protein Data Bank (PDB) Sstatistics shown that about (presently about 2,000 testimonies) of antibody configurations are accessible. Though Assembled data base of these PDB statistics, the comparative specific characteristic of antibody against viral inefection can be projected. The significant developmet and advancement in NAbs can be documented to can make available profile for researcher will be key for the vaccines counter to SARS-CoV-2. The crucial residues of boundary between an antibody and the antigen can be improved to yield in elevation affinity [25]. Numerous current computer cropping models have been used to guess the interface between S protein and human ACE2 [21] or antibodies [26]. The studies Int. J. Biol. Sci. 2020, Vol. 16 http://www.ijbs.com 1722 exposed the significant finding that SARS-CoVspecific CR3022 antibody could cross-react to SARSCoV-2.

Via Oligonucleotides against 2019-Ncov RNA Genome

Via Oligonucleotides against 2019-Ncov RNA Genome In addition to targeting the extracellular proteins of 2019- nCoV, the RNA genome itself can be targeted to be dispersed. The recently identified published 2019-nCoV genome sequence (GenBank: MN908947.3) could be consider another strategy Then, is it the use of small interfering RNA (siRNA) or antisense oligonucleotides (ASO) to fight the virus targeting its RNA genome [27]. The first problem with this strategy is unknown sequence of RNA domain of Cov-2109 Isolating preserved classifications is crucial before in direction to adjust siRNA leveling and reduce viral outflow of the oligonucleotide strategy. The comparative genome homology study of 2019-nCov will be significant to identify conserved sequence .The delivery of oligonucleotides into the lungs would be second big challenge for For this purpose lipid nanoparticles can be effective delivery vehicle to the lungs [28]. It is still unclear how much siRNA’s or ASO’s delivered within the lungs would be effective to stop the infection. For example, if lungs had siRNA or ASO 25% of alveolar epithelial cells that competence strength be a pronounced achievement over for traditional gene therapy, but would scarcely mark any metamorphosis in an epidemiologic infection [29]. Such siRNA candidates description correspondingly expose in case of failed Ebola trials, while its preclinical success in animal models. [30] Finally, if someone supposed that siRNA was result oriented clinically, but to to a large infected population there is inadequate capacity of SiRNA in manufacturing drug. Existing siRNA and ASO treatments are manufactured for rare diseases, and there are no available resources existing to manufacture the medications quickly [31].

Chemotherapeutic Alternatives for SARS-Cov-2 Infection

To handle the infected patients there is no prescribed clinical drug or vaccine developed or yet permitted by authorities Precautionary and life supporting treatments are presently deliver to infected patients .These prescription and set of established therapies include , antibiotic treatment along with oxygen therapy and further and antifungal treatment, extra-corporeal membrane oxygenation (ECMO) etc. according to symptoms of patients [31]. The seven antiviral drugs on Vero E6 cells in vitro were evaluated by Wang et al against SARS-CoV-2 infection, chloroquine, remdesivir (GS-5734) favipiravir (T-750), penciclovir, nitazoxanide, nafamostat, ribavirin, nitazoxanide, nafamostat [32]. The anti-malaria drug chloroquine and remdesivir were found more effective with low cytotocity as compared other seven drug treatments. The concentration (EC50) for chloroquine and remdesivir were 0.77µM and 1.13µM respectively which showed better improvements in the patients. Chloroquine is found effective in Vero E6 cells at different stages of SARS-CoV-2 infection (viral entry and post-entry stages) whereas s at post –entry satge remdesivir is more ecffetcive.

The antiviral activities of Chloroquine as a drug used for a malarial infection with potential broad-spectrum are established in the past [33]. The previous successful clinical trial indicates that with EC90 (6.90 µM) in Vero E6 cells is clinically achievable against SARS-Cov with significant results [27]. While Remdesivir as a drug presently under consideration which was effective during SARS-CoV and MERS-CoV in the past [34]. Remdesivir improves the functioning adenosine analogue and targeting RdRp, which results in in early expiry of the virus transcription. The most suitable trial of EC90 in Vero E6 cells is 1.76 µM with remdesivir against SARS-CoV-2 in nonhuman primate experiment is achievable [34]. In the United States, it is encouraging to note that treatment with remdesivir against viral infection was recommended to the patient on the day 7 without any adversarial events witnessed. The patient’s clinical symptoms improved on day 8 and the earlier condition wiped out, indicating the remdesivir capacity be effective to the treatment of SARS-CoV-2 infection. However this result should be taken with attention and care as this is only single case study and a proper trial control was lacking [34]. Presently, chloroquine and remdesivir are under phase 3 clinical trial and open- label trial for treatment of SARS-CoV-2 infection respectively. Initial results displayed that chloroquine phosphate had deceptive efficiency in handling of COVID-19. However, consideration required be taken during clinical practice of chloroquine as its overdose is exceptionally terrible without known solution [34].

Conclusion

SARS-CoV-2 is an developing threat and evolving infection, lacking actual treatment and existing drug or vaccine for instant management. The current mortality rate 2.3% of SARS- CoV-2 which is extremely alarming due to large number of infected patients could result in failure of health system of many states within short period of time ,and its strong apprehension that mortality rate might increase with of passage of time if defensive measures not taken in time. In addition, finical assistance is required to research groups to prepare antiviral drug within short span of time. In the meantime, to avoid the epidemic of this and other novel viruses in future. Guideline should be vigorously adopted by states to forbid the trade of uninhabited animals in food staff, because they are conceivable intermediary host(s) of several viruses. During the unexpected existing outbreak to deal with patients, Nabs therapeutic option remains at high significance .In coming couple of months Nabs therapeutic approach and its understanding mechanism may offer potential proposal for speedy progress of antibody therapy and vaccine for SARS-Cov-2.

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