An Update on SARS-CoV-2: Damage-response Framework, Potential Therapeutic Avenues and the Impact of Nanotechnology on COVID-19 Therapy

The appalling COVID-19 pandemic outbreak has become a major cause of mortality in 2020. The COVID-19 is caused by a dreadful coronavirus called nCoV (SARS-CoV2). The term “coronavirus” (CoV) originates from the Latin term corona, which means “halo”/ “crown,” as the virus carries the crown-like projections (spikes) on its surface. Coronaviruses are a large group of viruses causing mild diseases to severe respiratory and gastrointestinal diseases. This review describes the overview of COVID-19, including the origin and reservoir of SARS-CoV2 and the genomic sequence of SARS-CoV2 compared to other coronaviruses. Furthermore, major events of the COVID-19 outbreak, reported confirmed cases, death cases, and case fatality rate (CFR) of covid-19 since its beginning until now, and different facts about fatally potential beta coronaviruses are also discussed in detail in this review

The 2019-nCoV RNA genome is highly protected by its unique structure equipped with mechanistic spike proteins on its surface. Its RNA genome contains almost all 14 Orfs encoding for at least 27 proteins. An Orf is a part of genetic material that can undergo translation and produce proteins. Four structural proteins (SPs) likely spike (S), envelope (E), membrane (M), and nucleocapsid (N) are present in 2019- nCoV and afford its structure. In this chapter, we have discussed in detail the virology of 2019-nCoV including structural proteins (SPs), accessory proteins, non-structural proteins (NSPs), genomic structure, and its components. The role of SPs, accessory proteins, NSPs of 2019-nCoV is discussed and this review also explains, how the interaction of 2019-nCoV occurs with that of hACE2. Additionally, topics such as stabilization of virus-binding hotspots on hACE2 by 2019-nCoV, the role of thioldisulfide interchanges in the interplay between 'S' protein and hACE2, and the similarity (in terms of amino acid sequence homology) (%) of 2019-nCoV with SARSCOV are discussed. 

An important keynote that should be kept in mind is that to curb the spreading of the SARS-CoV-2 virus, one should understand how it enters host cells. This review provides deep insights into mechanistic intervention approaches of 2019- nCoV that target its host cell entry mechanisms. Majorly, there are three entryways for 2019-nCoV to target and infect the host cell, which is highly expressed with ACE2. The ‘S’- priming of TMPRSS2 associated cleavage is the primary entryway for a virus to access the targeted host cell via mediating the fusion process. The second way for virus entry is through the endocytosis phenomenon. The third way for virus entry is S pre-priming or S pre-cleaving of furin mediated fusion. Recent studies have proved that S1/S2' is a proteolytic cleavage site responsible for mediating viral entry. Hence, several protease inhibitors could be the potential targets to block proteolytic cleavage of the spike protein. This review describes the different entryways of 2019-nCoV and the impactful role of TMPRSS2 and furin host enzymes for a virus to get access into the targeted host cell; pre-fusion and post-fusion conformational states of 2019-nCoV spike protein; the role of viral suppressors of RNA in host immune evasion and the role of SPs, NSPs, and Orfs of 2019-nCoV in host immune evasion (host IFN response). Mutations of 2019-nCoVand its variants are reviewed in this article. 

The epidemiology of COVID-19 infection will be understood by the relationship between the intensity of action on public well-being and the rate of its transmission control. The virus is a chemical substance that is vulnerable until it invades the living body. The molecular assembly of the virus contains RNA genome and proteins. When 2019-nCoV enters the host cell of the living body, it continues its progeny by the replication process. It starts to make molecular assemblies for every new virion produced through replication and transcription. Though the incubation time is accounted for to range between 1 to 14 days, the median incubation period is 5 days. According to a recent survey on COVID-19 patients, 80 percent of patients are asymptomatic. This book chapter describes the life cycle and spread of 2019-nCoV, CFR, clinical manifestations, diagnosis, and prevention of COVID-19. 

 Etiology means the causation of a disease, where one or more factors are combined to cause the illness. In the case of COVID-19, etiological studies are helpful to determine the factors causing illness and they are required to pave the way for advanced treatment options. The main etiology for COVID-19 is immunopathogenesis which can be explained in terms of different stages of infection. This book chapter summarizes the etiology of COVID-19, different stages of COVID-19 infection, and the innate and adaptive immune response of the host to 2019-nCoV. In the early stages of infection, mild viral infection targets the nasal epithelial cells, followed by bronchial epithelial cells, and alveolar pneumocytes. In the moderate type of infection, Type-II pneumocytes are induced by the associated viral pyroptosis that leads to the triggering of IL-1β inflammatory signals, which is regarded as a localized inflammatory response. In the severe type of infection, exuberant cytokine storm syndrome (CSS) causes inflammation of the lungs, enhanced vascular hyper-permeability, and diffuse alveolar damage (DAD). As a result of the above effects, the severe stage of infection is characterized by pneumonia, ARDS (acute respiratory distress syndrome), and ALI. The infection causes CSS hyper-inflammation which additionally causes SIRS (Systemic inflammatory response syndrome). This SIRS finally leads to septic shock and multiple organ damage. Organ dysfunction for the liver, heart, and kidney is another problem for patients. 

Numerous infectious diseases caused by microorganisms that rarely cause disease in natural, stable immunocompetent hosts emerged in the late 20th century. The existence of these diseases demonstrates that current principles of pathogenicity and virulence fail to account for the fact that microbial pathogenesis is influenced by both the microorganism and the host. To overcome this impediment to studies on the host and microorganism interactions, a new theoretical approach is addressed to understand microbial pathogenesis known as DRF. COVID-19 is introduced as the third most pathogenic strain in the human population, leading to the deaths of millions of people. Therefore, it is necessary to understand the key pathogenic pathways at the molecular level and identify the targets to develop the treatments strategies for COVID-19 infected populations. In this chapter, we have highlighted the different COVID-19 pathogenesis pathways along with targets and their role in the pathogenic conditions at molecular levels. The DRF provides a lens to understand COVID-19 pathogenesis and consider how potential therapies could alter the disease's outcome by focusing on mechanisms of host damage, especially immune-mediated damage. 

Currently, there are no treatment options for the deadly emerging COVID19 infectious disease. The process of identifying new potential clinical applications for existing licensed and approved drugs is referred to as “drug repurposing.” It is also known as drug repositioning or drug re-profiling, or drug re-tasking, which is widely regarded as both cost-effective and efficient. Since few drugs have absolute selectivity of action, many other drugs have the potential to work against other diseases or new diseases. Clinical trials should begin with Phase III or IV studies because these trials use substances with proven biochemical and physiologic effects (which were already proven in Phase I and II clinical studies), potentially saving money and time. Hence, it is regarded as a useful technique for drug discovery because it takes less time and money to identify a therapeutic agent. This review summarizes the various repurposed drugs and possible new avenues for drug discovery to combat COVID-19. The Casirivimab and Imdevimab combination (Ronapreve) is approved for COVID-19 disease treatment based on regulatory reliance on the USFDA and EMA. 

COVID-19 disease is still affecting millions of people due to its high infectivity rate and attack rate. The host body's immune response to 2019-nCoV is one of the major factors to cause disease more severe, leading to cytokine storm syndrome (CSS). In fatal cases of COVID-19, pathological testing has confirmed the presence of immune hyper-activation, leading to acute respiratory distress syndrome (ARDS) and collateral tissue damage. Furthermore, rational control of 2019-nCoV immune responses, including boosting antiviral immunity while reducing systemic inflammation, may be crucial for effective and successful treatment. Hence, immune therapy is one of the best choices to combat immunopathogenesis-derived COVID-19 disease. We present possible immunotherapies based upon the immune response to 2019-nCoV and dysfunction of the immune response of CSS. Correct immunomodulation may be useful for severe or critically ill COVID-19 patients. Moreover, immunomodulators usage, either immunosuppressants or immune enhancers, will depend on the progressive course point of COVID-19 disease and the immune status of that patient. In this entry, we reviewed the various immunotherapeutic strategies, including current investigational candidates of natural immune modulators, convalescent plasma therapy, monoclonal antibodies therapy, IFN therapy, and intravenous immunoglobulin (IVIg) therapy. The main aim of this review article is to address the current findings and experience in immunotherapy against COVID-19. 

Nanoscience deals with the study of materials at nanoscale dimensions. It has been shown that modernizing drugs to a nanosized delivery system will afford fruitful outcomes with enhanced efficacy against the virus, reduction of the drug dose and improved targetability with enhanced/sustained bioavailability, If the drug dose is reduced, the dose-related side effects are reduced. Dose reduction through nanotechnology also limits non-target tissue toxicity. Hence, nanotechnology has remarkable potential in the pharmaceutical industry. Due to their small molecular level of tunable size, nanopharmaceuticals (in the form of nanoparticles) will easily enter the cells or tissues. The case of COVID-19, they interact with the virus and act accordingly and might inhibit the viral processes of 2019nCoV in COVID-19. 

Vaccines are life-saving immune biologicals. COVID-19 vaccines are administered into the body to attain the acquired immunity against the disease-causing virus 2019nCoV. The primary incentive of COVID-19 vaccines is to prevent symptomatic illness as well as severe illness too. Getting vaccinated with COVID-19 vaccines will decrease the risk as well as the duration of 2019nCoV infection, i.e., a decline in mortality, as proved in an experimental study conducted at the European Institute of oncology by Italian scientists. Many vaccine candidates are in phase III and phase IV trials with almost 95% efficacy in preventing symptomatic COVID-19 infections. According to official records from the national health agencies, 878.16 million doses of COVID-19 vaccines have been administered to the public as of April 16th, 2021, and 6.31 billion doses of COVID-19 vaccines have been delivered worldwide as of October 2nd, 2021. This chapter reviews the number of vaccines candidates’ ongoing, approved, and indispensable role played by the Indian government in vaccine supply to the global market. 

The knowledge and lessons learned from the prior severe acute respiratory syndrome (SARS) epidemics were inadequately materialized and mandated superior techniques and strategies in the health care sector. Currently available preventive and therapeutic management options are inadequate to deal with this pandemic of COVID19. Consequently, the phenomenon of excessive cytokine and chemokine storm clearly depicts a predominant dysregulation of host immune defense. Hence, the implication of optimal immunity boosters to defend against viral infections has been considered effective in addition to balanced nutrition to curtail the damage to the lungs. Plantbased natural products, including extracts, enriched fractions, essential oils, photo molecules, flavors, and fragrances, have attracted both pharmaceutical as well as cosmetic industries. In this chapter, we have comprehensively highlighted the significance of restructured immunity in the prevention of COVID-19. c-ATP (Cellular Adenosine Triphosphate) levels may potentially be considered as a decisive element for maintaining the innate immunity shield against the SARS-CoV-2 infection. Furthermore, implication of natural products, like Withania somnifera, Tinospora cordifolia, Curcuma longa, Glycyrrhiza glabra, and Andrographis paniculata, has been validated by the decipherment of their molecular mechanisms in immunomodulation. We propose the phospholipid complexation technique coupled with 3D printing technology to surmount the physicochemical and biopharmaceutical hurdles in order to scale up the use of phytopharmaceuticals with desirable immunomodulatory potential.