key: cord-1024811-3jiwcqfa
authors: Dubey, Ankit Kumar; Singh, Aakansha; Prakash, Shardendu; Kumar, Manoj; Singh, Ashok K.
title: Race to arsenal COVID-19 therapeutics: Current alarming status and future directions
date: 2020-10-27
journal: Chem Biol Interact
DOI: 10.1016/j.cbi.2020.109298
sha: fe61ddb14f6ea2147dbc5904c3d6e31ee9d8e1e5
doc_id: 1024811
cord_uid: 3jiwcqfa

The on-going pandemic of COVID-19 wreaked by a viral infection of SARS-CoV-2, has generated a catastrophic plight across the globe. Interestingly, one of the hallmarks of COVID-19 is the so-called ‘cytokine storm’ due to attack of SARS-Cov-2 in the lungs. Considering, mesenchymal stem cells (MSCs) therapy could contribute against SARS-CoV-2 viruses attack because of their immune modulatory and anti-inflammatory ability linked to their stemness, to the arsenal of treatments for COVID-19. Another novel therapeutic strategies include the blockade of rampant generation of pro-inflammatory mediators like acute respiratory distress syndrome (ARDS), degradation of viral protein capsids by PROTACs, composed of Ubiquitin-proteasome framework, and ubiquitination-independent pathway directing the SARS-CoV-2 nucleocapsid protein (nCoV N) and proteasome activator (PA28γ), etc. This review is consequently an endeavour to highlight the several aspects of COVID-19 with incorporation of important treatment strategies discovered to date and putting the real effort on the future directions to put them into the perspective.

The COVID-19 disease has become a household name, which puts fear into everyone's heart and mind. It gained fame due to how quickly it spread around the world since its birth in Wuhan city, China. It felt like almost overnight, this disease caught on globally, bringing both business and travel to a grinding halt and the government tried to curb its spread among our citizens. At any given time, hundreds of people are rushing into an emergency room nearby looking for urgent care trying to fight for their lives. COVID-19 manifests itself as a respiratory illness that is quite like a flu. It took doctors and scientists a few weeks to distinguish between the COVI-19 and normal flu, as both diseases have the same means of transmission and share some key symptoms. This similarity between both the diseases generated some confusion when the pandemic first broke out early this year because patients with COVID-19 mistook it as an ordinary flu.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread quickly to 213 countries and caused a large scale COVID-19 pandemic. Presently, the newly identified SARS-CoV-2 has caused a high mortality rate with tens of thousands of positive cases across globe, posing a grave threat to public health. COVID-19 has caused severe human pneumonia since the beginning of the 21st century [1] .

Initially, the world health organization (WHO) alluded the term 2019 novel coronavirus (2019-nCov) to underline the spread of this infection, which was officially turned into COVID-19 caused by SARS-CoV-2 virus [2] .

Importantly, the availability of clinically approved vaccines or specific therapeutic drugs for COVID-19 is still awaited. Furthermore, to elucidate the pathogenesis, epidemiology, and to identify potential drug candidates, extensive researches is urgently needed endowing to the discovery of effective therapeutic strategies [3] . At present, various diagnostic kits to test for COVID-19 and diverse ranges of clinically effective "repurposing therapeutics" are available and accessible. Furthermore, various healthcare organizations have initiated to formulate vaccines to prevent COVID-19 [4] . A large subfamily of singlestranded positive RNA viruses enveloped under the viral coat carrying one of the biggest genome sizes of around 30-32 Kb is capable of infecting organisms in the wild as well as the humans. [5] . Studies suggest that these viruses fall under the category of Coronavirinae subfamily being a part of the family Coronaviridae and the order Nidovirales [6] , which splits into three distinguished genera (α-, β-, and γ-coronavirus) which are affirmed by the antigenic property and genome sequencing. Further, international committee on scientific categorization of viruses (2009) added another genus named δ-coronavirus, which was suspected to be [50] . Patients diagnosed with COVID-19 displayed irregular breathing counts, and elevated pro-inflammatory cytokines in plasma [31]. Some of the patients may show variation in the counts of leukocytes and drop in the lymphocyte's levels [51] . Mainly if they are elderly or have some pre-existing health condition, patients may experience breathing difficulties. In such cases, the situation may need the patient to hospitalize. In worsening cases, the person may experience a condition where the pleural cavity of the lungs is filled with fluids, leading to a situation of acute respiratory distress syndrome (ARDS). Further, the development of the disease ends in the worsening of the symptoms, and at this factor, the patient is shifted to ICU. Patients with milder symptoms probably have more abdominal pain and lack of appetite [30]. However, the signs in the earlier days of the infection are hard to find out. Symptoms reported ranged from mild to severe disease and death due to confirmed coronavirus disease 2019 [52] . The overview of systemic progression of the COVID-19 symptoms from the early stage to the fatality stage with the recovering phase is summarized in Table 2 3. DIAGNOSIS Nevertheless, the test's reliability is uncut, as the PCR can only identify the virus if it is present in the suspect's sample. Consequently, output about the infection becomes uncertain, leading to sometimes falsenegative results depending upon the concentration and sensitivity [63] . Chest X-Ray may be other diagnostic criteria. C.T. imaging shows ground-glass opacities, bilateral infiltrates, and sub segmental consolidation, even in cases with no clinical evidence of respiratory tract infection (asymptomatic), considering being sensitive and specific diagnostic approach [64] 

More cases of COVID-2019 are coming up with the passing of each day, and the fear of the novel coronavirus unfortunately has true becoming a pandemic disease. Treatments provide doctors with resources to support the patients to produce a vaccine. Therefore, the development of vaccines at the earliest is of the utmost to curb the disease. Further, to understand the host, genomics, epidemiological links, and transmission modes of nCoV, constant efforts are being made at international, national, and individual levels [68]. Globally, drug manufacturers, research labs, and other organizations are producing several specific kinds of pharmaceutical drugs for COVID-19 therapy. Potential drugs include medications already employed or tested for the diagnosis of certain diseases and recently discovered or specially developed medicines ( Figure 4) J o u r n a l P r e -p r o o f

Drug repurposing also known as drug reprofiling or repositioning that assures to recognize antiviral agents for the novel coronavirus disease in a transient fashion. We also propose a perspective that antiviral combinations with a 'double hit effect' may present the best possibility of positive result and clinical translatability. Drug repurposing is a budding approach where existing medicines, already tested on safety parameters in humans, are rationalized to fight difficult-to-treat diseases. Such repurposed drugs may conclusively not yield a substantial clinical benefit when used individually but scrupulously combined cocktails could potentially be very effective, as demonstrated for HIV in the 1990s; the pressing challenge now being which combination.

Based on the early phase clinical trials testing, broad-spectrum antiviral agents (BSAAs) that have been 

The poor potency of hit compounds as single agents is one of the constraints of phenotypic screens since their maximal tolerated dose is many times sub therapeutic for the new indications being focused [86] . One way to J o u r n a l P r e -p r o o f elude this concern is to assess two or more drugs acting on different cellular signaling pathways involving viral replication with limited prolixity. One more approach, which may enable researchers to curb the spectrum of individual antimicrobials for emerging and re-emerging infectious diseases, is high-throughput 

The nucleoside analogues are significant class of antiviral agents that are now widely used in the treatment of numerous types of human viruses. The nucleoside analogues mimic naturally existing nucleosides, which function by terminating the nascent DNA chain. 

The Spike (S) protein of the SARS-CoV2 exposed to the surface, mediates the entry of the pathogen into the host cells, which is the crucial target of antibodies neutralization upon infection [93] . ACE-2 and TMPRSS2 are the receptors, which mediates the fusion of the S protein of the SARS-CoV2 to the host cell. The fusion of the S protein to the ACE-2 receptor is by cleavage through TMPRSS2, which is essential for viral entry and spread of infection [94] . The majority of coronaviruses enter their target cells via plasma membrane fusion, the endosomal endocytosis through the protease enzyme cathepsin L (CPL) that cleaves the S glycoprotein into two subunits S1 and S2, S2 fusion with the cell membrane is another entry mechanism [95] . Inhibitors of the TMPRSS2 and CPL activity may become a potential antiviral target thereby inhibiting the mechanism of cell-fusion and entry of the SARS-CoV2 into the cells. Figure 8 illustrates some of the cell fusion antiviral drug molecules against SARS-CoV2.

Neuraminidase inhibitors (NIs) are drug molecules targeting the category of influenza A and B viruses, which are currently in the therapeutic trial of COVID-19. NIs interact with the release of progeny influenza virus from contaminated host cells, a mechanism that protects new host cells from infection and thus avoids the spread of respiratory tract infection [96] . Figure 9 illustrates the common neuraminidase inhibitors in trial against COVID-19. 

In clinical studies, synthetic recombinant interferon α has been shown to be successful in treating SARS Table 3 illustrates some of the common interferon therapies in current clinical trials against COVID-19.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are aminoquinolines and implemented for over 50 years 

It includes the anti-inflammatory, antioxidant and antibody therapies. The disease's clinical characteristics include overproduction of reactive oxygen species that cause oxidative stress responses and lead to acute damage to the lung, which provides a new approach for the involvement of antioxidant therapy (NCT04466657). Vitamin C helps resist oxidative damage and increases immunity, improve antiviral ability and also avoid and manage acute lung infection and acute respiratory distress induced by certain respiratory viruses [96] . Figure 13 illustrates some of the antioxidants and anti-inflammatory drugs in current scenario of COVID-19 clinical trials.

Other strategy of the Immunoenhancing therapy includes the plasma therapy (convalescent plasma) and the monoclonal antibody therapy. Studies suggest intervention of plasma therapy and immunoglobulin on patients Table 5 explains the cellular therapy (stem cells) with the prolonged mechanism of action in different clinical trial against COVID-19 treatment.

The SARS-CoV-2 nucleocapsid protein (from now on, alluded to as nCoV N) represents the biggest extent of viral structure proteins and is the most plentiful protein in infection contaminated cells. An ongoing report displayed that a novel ubiquitination-independent pathway could administer the protein levels of nCoV N, and PA28γ could monitor the plethora of nCoV N by managing its endurance.

Additionally, study results revealed that PA28γ connects with nCoV N and advances its intracellular (Table 6 ).

In the present scenario, prompt transmission of SARS-CoV-2 across various nations has linked to fierce illness that make it very serious public health risk. In various controversies of strong researches, officially Presently, there is no approved treatment therapy for COVID-19 is available. However, virologists and frontline clinicians have been experimenting with virus based and host-based therapeutics since the outbreaks in the China. After a plethora of research search, we herein mention few pre-existing and novel therapeutic strategies for emerging scientists to discover drugs and/or vaccines to inhibit this viral outbreak that could assist in developing novel therapeutics for COVID-19 treatment.

For optimal outcomes, antiviral therapies like remdesivir, lopinavir/ritonavir and umifenovir could be initiated before the viral replication attains its peak level. Ribavarin is generally ineffective as a monotherapy and may be beneficial an add-on therapy.

J o u r n a l P r e -p r o o f 2. The use of corticosteroids should be limited to indicating comorbidities. Owing to lack of data in COVID-19, IVIG is usually not recommended.

Due to the conflicting outcomes in coronavirus studies, the efficacy of interferon is still unclear.

the benefits outweigh the risk of dysrhythmias remain inconclusive.

One of the great signs of COVID-19 is the so-called 'cytokine storm' due to attack of SARS-Cov-2 in the lungs. A cytokine family member Interleukin-6 (IL-6) inhibitors might be valuable for patients who developed cytokine discharge syndrome. Considering, mesenchymal stem cells (MSCs) therapy could contribute against SARS-CoV-2 viruses attack because of their immune modulatory, antiinflammatory, and restorative ability linked to their stemness to the arsenal of treatments for COVID-19.For potential clinical recovery, remdesivir might be regarded early in the course of illness expeditiously before disease progression. Before concluding on efficacy, more well-designed RCTs are warranted in COVID-19 therapies.

Apart from mediating the virus entry, ACE2 also displays protective role in the pathophysiological process of virus-induced ALI but the sequential role of ACE2 still remains unclear in the whole disease process and high-quality clinical trials and real-world data are potentially required to answer the question.

Although, in view of its key role in disease pathogenesis and pathophysiology, ACE2 has inspired comprehensive interests and plan of action targeting ACE2 and its ligand-COVID-19 spike protein;

this might render novel method in the prevention and management of COVID-19. 

Scientist should also work on investigating molecules that may target autophagy. Blocking of autophagy inhibits virus entry into cells, however, antigen presentation by macrophages blocks the activation of adaptive immunity on T cells as well as B cells. Consequently, the autophagy inhibitors would be best administered after achieving the adaptive immune response against the COVID-19, which often takes almost 5-6 days after the onset of disease.

Scientist should target human proteases involved in activation "Viral Spike protein". They may be transmembrane proteases, secreted proteases and intracellular endoplasmic reticulum (ER) proteases.

Although the researches are conducting on exploration of human proteases that might activate and cleave SARS-CoV-2 Spike protein, the intracellular ER proteases can continue to activate Spike protein and induce viral membrane fusion after initial endocytosis activated by extracellular proteases.

Few drugs having ability of blocking extracellular proteases (For instance; camostat, nafamostat, and cobicistat) are now in clinical trials.

The COVID-19 pandemic has emerged as the biggest public health threat with a potential to end up rivalling 

Authors declare that there is no conflict of interest. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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