key: cord-0831550-3zy5dgxz
authors: Pooladanda, Venkatesh; Thatikonda, Sowjanya; Godugu, Chandraiah
title: The current understanding and potential therapeutic options to combat COVID-19
date: 2020-05-08
journal: Life Sci
DOI: 10.1016/j.lfs.2020.117765
sha: 6d36596c43f5f3ac4981f36a75765d62e68538f4
doc_id: 831550
cord_uid: 3zy5dgxz

The ongoing wreaking global outbreak of the novel human beta coronavirus (CoV) pathogen was presumed to be from a seafood wholesale market in Wuhan, China, belongs to the Coronaviridae family in the Nidovirales order. The virus is highly contagious with potential human-human transmission which was named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread across six continents and emerged as a global pandemic in short span with alarming levels of spread and severity. This virus associated symptoms and infectious respiratory illness is designated as coronavirus disease 19 (COVID-19). The SARS-CoV-2 possesses enveloped club-like spike protein projections with positive-sense large RNA genome and has a unique replication strategy. This virus was believed to have zoonotic origin with genetical identity to bat and pangolin CoV. In the current review, we introduce a general overview about the human CoVs and the associated diseases, the origin, structure, replication and key clinical events that occur in the COVID-19 pathogenicity. Furthermore, we focused on possible therapeutic options such as repurposing drugs including antimalarials, antivirals, antiparasitic drugs, and anti-HIV drugs, as well as monoclonal antibodies, vaccines as potential treatment options. Also we have summarized the latest research progress on the usage of stem cell therapy, human convalescent serum, interferon's, in the treatment of COVID-19.

Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), Two-pore channel subtype 2 (TPC2), and cathepsin L are considered crucial. The availability of proteases in the host such as furin, TMPRSS2, trypsin, cathepsins and human airway trypsin-like protease (HAT) cleave spike proteins that largely determine whether CoVs enter cells through plasma membrane or endocytosis (25) .

For fusion and the release of viral RNA genome into host cytoplasm, the virion undergoes various modifications by lysosomal cysteine proteases, cathepsin L and cathepsin B in the endolysosomes and this step is found to be highly pH-dependent. Highly acidic endosomal pH is needed for the fusion and eventually uncoating of the envelope (25) . Further, the viral genomic RNA is released into the cytoplasm and translates into two viral replicase polyproteins, pp1a and pp1ab that encode non-structural proteins, and form replication-transcription complex (RTC) (26) . Continuously the polymerase produces a nested set of subgenomic mRNAs and finally translates into relevant viral proteins. Furthermore, endoplasmic reticulum and Golgi together assemble the newly formed genomic RNA, envelope, nucleocapsid and glycoproteins in vesicles thereby the virion fuses with the plasma membrane to release outside the cell. The envelope protein E has conserved the functional features, such as ion-channels and a PDZ-binding motif (PBM) which is required to induce virulence (27). The virus can infect ACE2-bearing cells in organs such as lung, esophagus, mouth, heart, intestines, bladder, and kidney (28) (Figure 3 ). J o u r n a l P r e -p r o o f from BAL or throat swab from nine patient samples and found interesting observations that the SARS-CoV-2 genome sequences exhibited more than 99·98% sequence similarity among different patient samples tested, which shows that the smaller degree of diversification. They also found an 88% similarity to bat derived SARS like CoVs including bat-SL-CoVZC45 and bat-SL-CoVZXC21. Interestingly, this study also compared the similarity to SARS-CoV and MERS-CoV, where it was observed a 79 and 50% similarity which indicates that these viruses are distinct to SARS-CoV-2. Surprisingly, in late December Wuhan bat species were in hibernation and were not available for sale in the seafood market. This report also speculates that and various evidences has been described in Table 2 .

SARS-CoV-2 is highly contagious with powerful transmissibility. The current evidence suggest that human-human transmission of SARS-CoV-2 is mediated by coughing or sneezing from the infected individual through respiratory droplets (droplet particles >5-10 μm in diameter) in close contact (within 1 meter) or as droplet nuclei (particles <5μm in diameter) which can remain in the air for long periods and be transmitted to others over distances greater than 1 meter. The transmission is also possible with the indirect contact with surfaces in the immediate environment exposes to the mucosa by nose and mouth or conjunctiva (eyes) for the viral entry During an emerging pandemic outbreak of an infectious disease, it is essential to know the level of transmission and the contagiousness which can be estimated by "R naught" (R0), a mathematical term which is the basic reproduction number that determines the average number secondary cases who are previously free of infection gets infected by one sick host. If the R0 is less than one the existing infection causes less than one infection, in such cases the spread J o u r n a l P r e -p r o o f declines and disappears. If R0 value equals 1, each existing infection causes one new infection. If R0 is more than 1, each existing infection may spread on an average more than one individual which may lead to dramatic increase in transmission and may result in epidemic (45). The R0 value of SARS was ranging from 1 and 2.75, while the R0 of MERS-CoV was <1. The R0 of SARS-CoV-2 in Wuhan, China was estimated to be in the range of 2.24 to 3.58 in the early phases (46). Steven Sanche et.al found that R0 of SARS-CoV-2 is likely to be 5.7 (47). Data from six different studies estimated that R0 could range from 1.5 to 6.49, with an average of 4.2.

However, WHO estimates R0 from 1.4 to 2.5 (48). COVID-19 affected people patients serum show SARS-CoV-2 nucleic acid viral load (RNAaemia)(49) and exhibits the symptoms which include fever, coughing, sneezing, throat pain, anorexia, chest pain, diarrhoea, nausea, vomiting dyspnea, the other characteristics most commonly exhibited are prolonged prothrombin time and lymphopenia. However, there are documented additional fatal complications such as acute respiratory distress syndrome (ARDS), acute cardiac injury, and incidence of grand-glass opacities (an area of increased attenuation in the lung on computed tomography (CT) with preserved bronchial and vascular markings in the periphery of the lungs with haziness overlying an area of the lung) (50) in some cases which lead to increased mortality rate (51). Recent evidence suggest that 97.5% of infected individuals develop symptoms within 11.5 days and the median incubation period to develop symptoms was estimated to be 5.1 days and 101 out of every 10000 cases were found to develop symptoms after 14 days of active monitoring or quarantine (52).

By Jan 2, 2020, SARS-CoV2 complications were studied in a case series on initially hospitalized 41 COVID-19 confirmed patients. Among the cases 73% of the infected patients were men, 20% diabetes, 15% had hypertension and 15% of cases had other cardiovascular diseases. All patients J o u r n a l P r e -p r o o f in common had pneumonia. The other common symptoms were fever, myalgia or fatigue, cough, and the less common symptoms were hemoptysis, sputum production, lymphopenia, dyspnoea, diarrhea, and the other complications are ARDS and secondary superinfections (53).

Cytokine storm refers to an aberrant or uncontrolled release of proinflammatory cytokines that lead to acute inflammation and pyrexia, which begins at a local site and spreads throughout the body via the systemic circulation. The previous out breaks of SARS-CoV and MERS-CoV have witnessed acute lung injury (ALI), ARDS and death which is accompanied by rapid virus replication that led to excessive inflammatory cell infiltration and cytokine storm (54). Similarly, now in COVID-19 outbreak, elevated cytokine levels are observed in critically ill patients. A case report by Chen et al, has observed a markedly higher levels of TNF-α, IL-10, IL-2R, and IL-6, with remarkable reduction in CD4+ and CD8+ T lymphocytes, nearly in all 11 severe cases tested as compared to 10 moderate cases. The reduction in T lymphocyte number may further reduce the production of IFN-γ (55). These findings are in line with Pederson et.al and Diao et.al which demonstrated that the depletion of T cells and dysfunction in COVID-19, which can be implicated with the cytokine storm through the activation of highly inflammatory macrophages that produce the inflammatory cytokines and may dampen adaptive immunity against SARS-CoV-2 infection. Also, an increase in the inflammatory indicators such as D-dimer and procalcitonin were found (56,57). Based on the clinical data by Hui Li many critically ill COVID-19 patients developed typical sepsis symptoms such as cold extremities, shock weak peripheral pulses and severe metabolic acidosis and hypothesized that the viral sepsis could be one of the critical clinical manifestations in cytokine storm. However, very little is known about the involvement of Toll like receptors (TLR) (58). In another case study, the COVID-19 patients plasma samples were analyzed for cytokines by multiplex assay, where IL-1β, IL-7, IL-10, IL-8, J o u r n a l P r e -p r o o f IL-9, basic FGF, IL1-RA, GM-CSF, G-CSF, IP-10, MIP-1A, MIP-1B, MCP-1, PDGF, TNF-α,   VEGF, and IFN-γ were found to be elevated in both (Intensive care unit) ICU and non-ICU   patients, while no apparent changes were found in the levels of IL-15, IL12p70, IL-5, Eotaxin, and RANTES when compared to healthy adults. On the other side, the higher plasma levels of IL-7, IL-2, IL-10, GSCF, TNF-α, MCP-1, MIP-1A, and IP-10 were observed in ICU patients in comparison with non-ICU patients. This data suggest that the disease severity might be through the involvement of cytokine storm with SARS-CoV-2 infected critically ill patients (53).

Another case series was on 138 hospitalized patients, where the symptoms are consistent with the previously mentioned case report, all of the 138 patients showed bilateral involvement, critical illness was seen in older patients with co-morbidities. Apart from these symptoms, prolonged prothrombin and elevated lactate dehydrogenase levels were observed in 80 and 55 patients, respectively. Another observation was a gradual increase in blood urea, creatinine levels, neutrophils and lymphocytes counts before death. The other major complications during hospitalization are shock, arrhythmia, ARDS, and acute kidney injury (59). Chen and colleagues based on a retrospective, single-center study on 99 cases (20), subsequently, Qian and colleagues reported that in 67.03% infected patients had multilobe infiltration in 53.85% patient population and an elevated levels of C-reactive protein (CRP) was seen, further in 15.39% patients elevated levels of procalcitonin was detected. Interestingly, in one case report COVID-19 had been detected from the rectal swab, who suffered from abdominal symptoms but tested twice negative by throat swab (60). Therefore, along with the antiviral therapy it may be crucial to use antiinflammatory agents in treating COVID-19 patients. Theoretically, corticosteroids may suppress lung inflammation, and they have been prescribed in 72.2% of ICU patients (61) but its efficacy in treating the cytokine storm in COVID-19 patients is still controversial as the concerns J o u r n a l P r e -p r o o f centered around their short-and long-term adverse effects as well as promotion of viral rebound and ARDS (62).Therefore, it is important to identify the cytokine storm in response to SARS-CoV-2 infection and the mechanism behind the cytokine storm. It would also be important to elucidate the role of anti-inflammatory agents against SARS-CoV-2 induced inflammation.

WHO Director-General constitutes a Public Health Emergency of International Concern for the outbreak of COVID-19, recommends the options to prevent the disease in new areas and possible reduction in human-to-human transmission to curtail its further spread that can be achieved by the strict quarantine, which involves the movement restriction or separation from the rest of the population with sustained and intense hygiene measures (63). Avoiding mass gatherings in enclosed spaces, maintaining the distance of at least 1 meter from any person with respiratory symptoms (e.g. coughing, sneezing); wearing a medical mask for an adequate level of protection combined with hand hygiene frequently by using an alcohol-based hand rub or soap is recommended. The people who develop a febrile illness or respiratory symptoms at any point during the quarantine period should be treated and managed as a suspected case of COVID-19 (64) . Healthcare personnel must use the personal protective equipment (PPE) such as N95 or FFP2 standard masks, gowns, gloves, eye protection shields to protect themselves, patients, and others when providing the care (65).

RAS and ACE2 inhibitors are widely used in treating patients with hypertension. As described earlier ACE2 is the target receptor for SARS-CoV-2 and is highly expressed in epithelial cells in J o u r n a l P r e -p r o o f the oral mucosa (66) . Additionally, this protein is widely expressed in immune reactive cells such as macrophages, lungs, blood vessels and intestine (67) . Clinical findings suggest that circulating ACE2 levels were significantly increased in diabetic and cardiovascular patients, however, this protein is aberrantly expressed with ACE inhibitors Lisinopril alone (68) .

But the ACE2 activity is not altered correspondingly, while cardiac ACE2 mRNA expression was increased with RAS receptor inhibitor Losartan. Combination of Losartan and Lisinopril did not affect the ACE2 activity compared with Losartan alone, but on other side, ACE2 mRNA was highly expressed with Losartan alone (69) . Thus there is a lack of correlation between up and down expression of ACE2 mRNA with ACE2 activity. However, there is a debate on the use of RAS and ACE inhibitors in SARS-CoV-2 pneumonia infections and few clinical trials are going on for the usage of Losartan among patients who have not previously administered with RAS inhibitors and are either hospitalized (NCT04312009) or not hospitalized (NCT04311177) (70, 71) . The selective ACE2 inhibitor DX600 might show beneficial results in SARS-CoV-2 infections; however its clinical significance in COVID19 has not evaluated (72) . Further, in one promising study, circulating recombinant human soluble ACE2 protein upon intravenous administration produced significant blockade of initial stages of SARS-CoV-2 viral entry and infections by preventing the binding of viral spike protein onto cell host cell surface ACE2 receptors (73) .

J o u r n a l P r e -p r o o f used to treat amebiasis (75) and other autoimmune disorders such as rheumatoid arthritis (76) and lupus erythematosus syndrome (77) . Chloroquine and its derivative hydroxychloroquine inhibit the heme polymerase in malarial trophozoites, preventing the conversion of heme to hemozoin. Plasmodium species continue to accumulate toxic heme, killing the parasite and exhibits antimalarial activity (78) . Whereas the antiviral activity of chloroquine is exerted by diffusing into the host cells and accumulating in endosomes, lysosomes and Galgi complexes, where it is converted into protonated form, then this moiety is deposited in organelles and further involve in raising the surrounding pH (79) . The raised pH in endosomes and lysosomes prevent viral fusion and inhibits the viral entry by endocytosis into the cells (80) . ACE2 is the target receptor for SARS-CoV and SARS-CoV-2 for viral fusion, however, chloroquine does not affect the ACE2 levels but downregulated the terminal glycosylation of ACE2 (79, 81, 82) . Insufficient Chloroquine/hydroxychloroquine has been used extensively to understand the mechanism of Nanoparticles uptake into cells. It was used as inhibitor of Nanoparticles uptake via endocytosis pathway. Similar kind of viral particle entry through endocytosis route is proposed to be inhibited by Chloroquine (83) . Artemisone found to be effective against human cytomegaloviruses, but effect of these compounds on SARS-CoV-2 needs to be evaluated (89,90). Moreover, the severe inflammatory cytokine storm observed in multiple organs may be curtailed by Chloroquine due to its immunomodulatory effects.

Azithromycin is a renowned antibacterial drug belongs to the class of macrolide antibiotics. patients.

The fluoroquinolone antibacterial drug Ciprofloxacin is used to treat respiratory tract infections.

Apart from its antibacterial activity, it can reduce the replication of polyoma BK virus.

Ciprofloxacin reduced the viral load with IC 50 value (50% virus inhibitory concentration) of 216.67 ± 16.7 μg/ml, whereas, Coumermycin showed the IC 50 value of 10.6 ± 3.9 μg/ml (96).

The aminoglycoside antibiotics including Neomycin, Kasugamycin, and Streptomycin inhibited herpes simplex, influenza A and Zika virus replication by upregulating the interferon-stimulated genes (ISGs) (97). The polyether antibiotic CP-44161 is recommended to treat varicella-zoster virus infections and also it inhibited the proliferation of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (97,98). However, these antibiotics were not tested on SARS-CoV-2. Few antibiotics which exhibit antiviral properties are described in Table 3 .

The US-FDA approved antihelmintic drug Niclosamide is also explored as an anticancer, antibacterial and antiviral agent. Also, it was found to be effective as a protease inhibitor in shedding the SARS-CoV and MERS-CoV replication and viral antigen synthesis was suppressed by Niclosamide at 1.56 μM (99,100). It might be a good pharmacological agent to treat SARS-

CoV-2 infections as well and studies may be designed to evaluate the same in vitro and clinical conditions (101) . The FDA approved antiparasitic drug Ivermectin is widely used as an essential medicine to treat lymphatic filariasis, strongiloidiasis, ascariasis, head lice, scabies, and river blindness etc (102) . Ivermectin was tested for its repurposing antiviral activity against SARS-CoV-2, where it has shown excellent antiviral activity. The in vitro results suggest that

Ivermectin reduced viral RNA load >5000 fold with 5 μM concentration at 48 h (103) . It might be a good repurposing drug in treating SARS-CoV-2 infections and further studies are required for this specific use.

An American biotechnology company Gilead Sciences developed the antiviral drug Remdesivir The nucleoside analogue Ribavirin has extensive activity against DNA and RNA viruses and it is used to treat SARS-CoV patients (114, 115) . The exact antiviral mechanism of Ribavirin has been studied for decades and it is still unclear. Ribavirin usage is associated the major side effect J o u r n a l P r e -p r o o f of anaemia which is found in 27-59% of patients. The importance of Ribavirin for fighting against SARS-CoV-2 was evaluated in combination with protease inhibitors and corticosteroids (116) . This drug has been showing significant results with Sofosbuvir and this combination is under the clinical trials (NCT01497366).

The nucleotide analogue Sofosbuvir is used to treat hepatitis C and it is recommended in combination with Ribavirin, Ledipasvir, and Voxilaprevir (117, 118) . Molecular docking studies of RNA dependent RNA polymerase model suggest that Sofosbuvir in combination with Ribavirin and Remidisvir could exhibit possible therapeutic effects in SARS-CoV-2 (92).

Basically, Sofosbuvir is a prodrug, which converts into active metabolite GS-461203 (2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate) and serve as a defective substrate for the nonstructural protein 5B (NS5B) of RNA dependent RNA polymerase and further inhibits RNA synthesis (119) . Sofosbuvir and other combinations will be tested in the view of adverse effects such as pruritis, upper respiratory tract infections, and lymphopenia (117) . The antiviral drugs which are under the clinical trials for treating COVID-19 are described in Table 4 .

The short term anti-coagulant, antiviral and antibacterial drug Nafamostat mesylate inhibits Spike protein induced membrane fusion in MERS-CoV and also researchers suggested that using Nafamostat alone or with combination of antiviral drugs could be a safe approach in treating COVID-19 (120, 121) .

The 166 amino acid sequence of Interferon alfacon-1 is produced by recombinant DNA technology, which is the class of non-naturally occurring type-I interferon (122) . Interferon alfacon-1 acts as anticancer and antiviral agent. The therapeutic effect of Interferon alfacon-1 J o u r n a l P r e -p r o o f was observed in leukemia, melanoma, HIV/AIDS related Kaposi's sarcoma, and hepatitis C (123) . It is also found to be effective in SARS-CoV and also tested in SARS-CoV-2 in combination with corticosteroids (124, 125) . Interferon alfacon-1 shows antiviral activity by binding to interferon receptors type 1 including IFNAR1 and IFNAR2c. Further, it initiates the dimerization and activates the Janus kinase 1 (Jak1) and tyrosine kinase 2 (Tyk2)

phosphorylation. The signal transducers and activators of transcription 1 and 2 (STAT1 and STAT2) bind to the phosphorylated IFNAR and initiate the expression of immunomodulators and antiviral protein expression including protein kinase R (PKR) and 2′-5′ oligoadenylate synthase (2'-5' OAS) (126) . Additional clinical studies are required to approve this drug for SARS-CoV-2 therapy. There are multiple reports on the antiviral activity of IFN-α and IFN-β, and combinations of IFN-α/β, IFN-β 1a and IFN-γ against SARS-CoV and these agents might be also effective against SARS-CoV-2 too, which need to be evaluated in suitable studies (127, 128) . to recover from day one and SARS-CoV-2 viral load was gradually decreased and the body temperatures were significantly decreased within three days. At day 9, it was reported that patients have started to take own breath without ventilation support. All the patients were symptomless, became stable and 3 out of 5 patients were discharged too (130) . Recently, the US-FDA allowed medical practitioners and physicians to use convalescent plasma in emergency to treat critical ill SARS-CoV-2 patients and few of the clinical studies are also initiated for the use of anti-SARS-CoV-2 and convalescent Plasma (NCT04321421, NCT04323800, NCT04325672) (131) .

Monoclonal antibodies are currently used for diagnostic and therapeutic purposes. Various Table 5 .

Our diet contains a lot of vitamins, minerals, carbohydrates, proteins, fats, and lipids and they Andrographolide is a diterpenoid isolated from Andrographis paniculata, which has been employed in treating various diseases such as cancer and inflammatory diseases (147) . Apart Quercetin is widely present in leaf vegetables, red onions, seeds, and grains, which is a plant flavonol from the flavonoid group of polyphenols and employed as a pharmacological agent in treating inflammation and cancer (149) . It has shown the antiviral activity against Dengue virus by inhibiting the viral replication without affecting its attachment and entry process (150) . Also The water soluble vitamin C (ascorbic acid) is profoundly available in lemon, oranges, amla, kiwi, guava, grapes, broccoli, cauliflower, and capsicum etc. Vitamin C is well-known as an antioxidant and inhibits the ageing process by enhancing the collagen expression, further, it involved in the wound healing process (154) . Apart from the antioxidant effects, Vitamin C involved in chemotaxis, phagocytosis and increases the reactive oxygen species to kill the microorganisms and also acts as an antibacterial agent. It also protects cells by clearing the nonfunctional organelles by apoptosis mechanisms. Also, it involved in proliferation and differentiation of B-and T-cells, which play a pivotal role in immune mediated reactions (155) .

expression ad reduced the MDA levels and increased the GSH levels and acts as an antiinflammatory agent (156) . Additionally, Vitamin C inhibits the lung fibrosis by reducing the IL-17 secretion and induced SOD levels (157) . Vitamin C also has a direct virucidal effect at higher concentrations and decreased the virus load of Ebstein-Barr virus (EBV) infected cells (158, 159) .

In general, vitamin C is considered as strong immune booster and must able to protect wide array of microbial infections. However, some reports suggest that ≥1 g per day vitamin C supplementation had no significant effect on common cold incidence. But, some evidence infers that vitamin C could have moderate preventive effects in low dietary intake groups or acute physical stress suffering people (160) . Based on the anti-inflammatory and antiviral properties,

clinical trials (NCT04323514, NCT04264533, NCT03680274, and NCT04326725) are ongoing for its therapeutic usage.

The crude extracts and active constituents of Bupleurum spp., Heteromorpha spp., and Scrophularia scorodonia, Lycoris radiata, Artemisia annua, Pyrrosia lingua, Lindera aggregata, Isatis indigotica, Torreya nucifera, Houttuynia cordata were found to be effective in treating SARS-CoV and these agents may also have effects in curing SARS-CoV-2 infections (161) . Few of the natural products and dietary supplements having antiviral activity are enlisted in Table 6 .

The biological preparation of vaccine is useful in attaining the acquired immunity against 

Calmette-Guérin (BCG) is primarily used to prevent tuberculosis (170) and other diseases such as leprosy (171) Table 7 . Table 9 about their anti-SARS-CoV and anti-MERS-CoV activity.

Over the past 50 years, in the pre-SARS era, many different CoVs have been identified that caused a wide variety of human and veterinary diseases. In particular, the human CoVs were found to cause mild respiratory diseases. In November 2002, SARS-CoV infection was emerged in Guangdong Province of China, identified to be fatal resulting in ARDS, which became a pandemic in 37 countries with over 8000 reported cases and 800 deaths (182) . This deadly SARS virus was found to be originated from horseshoe bats that transmitted to pangolins before reaching humans (183) . At that time no specific drugs or vaccines were available and only preventive measures were implemented to limit the transmission rate by maintaining social (193) J o u r n a l P r e -p r o o f 

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