Current Potential Treatment Strategies for the Deadly, COVID-19

Moumita Chowdhury¹, Debabrata Ghosh Dastidar¹, Abhijit Sengupta¹, Lopamudra Dutta¹

Introduction

Every dark cloud has a silver lining. It was until 2002 that corona was considered as a non fatal virus. Then it proved its fatality with rapid widespread of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 [1, 2] and Middle-East respiratory syndrome coronavirus (MERS- CoV) in 2012 [3]. Now in the year 2019, the entire world is facing the serious devastating effects of corona virus disease (COVID 19) on human lives, health system and economy due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [4, 5]. It was first reported to World Health Organization (WHO) on December 31, 2019. WHO declared the outbreak of COVID-19 as global health th emergency on 30 January 2020 and as global pandemic on 11 March 2020 [6]. It has become a serious pandemic threat worldwide and requires immediate solution. The outbreak of COVID 19 started in China in December 2019 and now it has affected every continent except Antartica.

st Globally, as of 31 December 2020, there have been 83,068,034 confirmed cases of COVID-19, including 1,812,208 deaths, reported to WHO [7]. Along with this, millions and millions of people’s lives are continuously being affected due to mandatory isolation. Thus COVID 19 outbreak has potentially brought major challenges and far reaching consequences on global health system and Coronavirus are spherical in shape and they contain singlestranded positive sense RNA covered with club shaped glycoprotein that project out from their surface just like a

Methodology

Extensive literature survey has been done to accumulate the data which can provide information needed for the treatment and prevention of COVID 19. The survey started with the papers published in high impact journals from several sites like Pubmed, Science direct, Web of science. The search was also done along the site of FDA, WHO, Clinical trial. The keywords used for the search includes COVID 19, treatment, prevention, drugs used, case studies, convalescent plasma, vaccines, current update on corona virus, current papers as well as case studies were the source of information. Current status of the treatment protocols were obtained from the website, clinical trial.gov.in

Transmission

The various routes of transmission for SARS-CoV-2 are through touch, via droplet, blood borne, airborne, oral, mother-to-child as well as animal-to-human transmission [13]. Saliva and respiratory secretions expelled by infected person during coughing, sneezing, talking causes by distribution of infectious droplet nuclei which remains suspended in air for prolong period and throughout long distances [18]. Contact with surfaces or objects which has been contaminated with virus from an infected person followed by touching mouth, nose, or eyes also transmits the corona virus. SARS-CoV-2 RNA have been detected in urine as well as in excreta of some patients where viable SARS-CoV-2 was found in the urine of a patient [19-22]. Some studies have detected SARS-CoV-2 RNA in plasma and serum but the virus has found to divide in blood cells at a very low rate. Some studies have shown that in few breast milk samples obtained from infected mothers, viral RNA fragments have been detected but they were not viable so breast feeding is not yet found to transmit the disease [23]. A SARS-CoV-2 infected person can transmit the virus 1-3 days before the onset of symptoms with the highest viral load around the day of onset of symptoms which gradually decreases over time [24-26]. Multiple studies have found that most people infect others before they themselves become ill [27]. The transmission can be prevented by identifying the suspect cases as fast as possible and isolating the infectious person.

Symptoms

COVID-19 affects people in different ways. Most people will develop symptoms within 5-6 days of infection but some may remain asymptomatic. Most common symptoms are fever, dry cough, tiredness. Other symptoms are body aches, sore throat, diarrhoea, conjunctivitis, headache, loss of taste or smell, skin rash and even discolouration of fingers or toes. Person with difficulty in breathing or shortness of breath, chest pain or pressure and loss of speech or movement requires immediate hospitalization [28]. It also causes acute respiratory distress syndrome (ARDS), acute renal injury, acute respiratory injury, septic shock and ventilator-associated pneumonia. In older patient or patients having diabetes, hypertension, cardiovascular disease, cancer are at major risk. In the most severe cases, infection can cause pneumonia, severe acute respiratory syndrome, kidney failure and even death [29].

Pathogenesis

After the virus enters the host cell, the viral RNA genome gets released in the cytoplasm and translates to form two polyproteins and structural proteins, after which the viral genome starts to divide [30]. Glycoprotein formed as the envelope gets itself inserted into the membrane of endoplasmic reticulum and genomic RNA and nucleocapsid protein combines to form nucleocapsid. As a result the viral particles develop to form endoplasmic reticulum-Golgi intermediate compartment (ERGIC). The vesicles loaded with viral particles fuse with plasma membrane releasing the virus [31]. Respiratory system is the major area targeted by COVID 19 infection causing severe pneumonia, RNAaemia, which combines the chance of ground-glass opacities, and acute cardiac injury [30]. High level of cytokines and chemokines were found to be present in the blood sample of COVID 19 infected patients. It was also found that high level of pro-inflammatory cytokines in COVID infected patients increased the severity of disease leading to admission in intensive care unit [32].

Treatment strategies

Lungs have greater number of alveolar epithelium cells expressing ACE2 which allows replication of corona virus in the lungs, making it the most targeted organ for COVID 19. The ACE2 receptor was found to express in kidney, endothelium, pharynx, heart and intestine [33, 34]. So a potential treatment targeting lungs can prevent the infection and its spread to other tissues. The spike protein, S on the surface of SARS-Cov-2 bind with ACE2 binding receptor in presence of TMPRSS2 for entering into the host cell and thus cause infection [35]. So a medicament which can prevent virus entry into the host cells by either inhibiting the protease or by inhibiting the binding of ACE2 with the virus will be effective against COVID 19.

Currently used drug under study for treatment of COVID 19

Remdesivir: Remdesiver has gained emergency use authorization for treatment against COVID-19 by US FDA. Remdesivir (also called GS-5734) is a monophosphoramidate prodrug of an adenosine analogue that has a broad antiviral spectrum coronaviruses [36, 37]. In vitro, remdesivir inhibits all human and animal corona viruses including SARS-CoV-2[37, 38]. Remdesivir acts by inhibiting SARS-CoV-2 replication in human nasal and bronchial airway epithelial cells [39].

Favipiravir: Marketed under the brand Avigan, the drug works by preventing the virus from replicating in cells. Favipiravir triphosphate is a purine nucleoside analogue, which acts as a competitive inhibitor of RNA-dependent RNA polymerase [40]. It has activity against influenza A and B, several agents of viral haemorrhagic fever and SARS-CoV-2 in vitro [41].

There are some drugs which affect viral host entry and interferes with viral replication and can be used against COVID 19 are listed in Table no. 1[42].

Removes viruses by enabling immune cells to engulf them prevents tissue damage produced by the sudden activity 2 Inhibition of (serine protease) TMPRSS2 activity 3 Affects viral fusion and uptake 4 Blocking or changing of the ACE2 receptor 5 Delivery of soluble ACE2 6 Inhibition of cathepsin B/L

Interference with viral replication

7 Interference with RNA‑dependent RNA polymerase 8 Inhibition of (cysteine proteases) 3CLpro and PLpro activity 9 and reduces the gathering of inflammatory inflammatory cells.

Current researches on clinical trials done on COVID-

19 1. An investigational monoclonal antibody, LY3819253 (LY-CoV555) was made by Eli Lilly and Company and discovered by AbCellera. LY-CoV555 is IgG1 monoclonal antibody (mAb), potent towards SARS-CoV-2 spike protein.

It blocks the attachment of virus preventing entry into human cells. The virus gets neutralized potentially which prevents and treats COVID-19. This antibody was isolated from the blood sample of a recovered COVID-19 patient.

Since this antibody is generated by immune system of a recovered patient, studies have found it to be effective against corona virus. It is injected into the vein of patients and samples are collected from the back of the nose at different time during the study to estimate the presence of virus in the body. A Randomized, Double-blind, Placeboth Controlled, Phase 2 is carried out in 400 patients from 17 th June 2020 to 5 November to study its efficacy and safety in Participants with mild to moderate COVID-19 illness [43].

Camostat mesilate Nafamostat mesilate Bromhexine Antiadrogen Chloroquine Hydroxychloroquine Hydroxychloroquine sulfate Chloroquine Hydroxychloroquine Recombinant human ACE2 E-64d, an epoxysuccinyl cathepsin inhibitor Miraziridine Tokaramide Quercetin Remdesivir (GS-5734) lopinavir/ritonavir Quercetin Bromhexine Chloroquine EC-18 (derived from Sika deer antler) cells and (Enzychem submits IND for trial of Covid-19 treatment) It has successful completed Phase 1 clinical trial with 40 th rd patients from 28 May 2020 to 23 August 2020 [44].

2. An investigational mRNA-1273 vaccine has been developed to prevent COVID-19, manufactured by modernaTX, Inc., and NIAID. mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated nucleoside modified messenger RNA (mRNA) -based vaccine that encodes for a full-length, prefusion stabilized spike (S) protein of SARS- CoV-2. A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study is carried out to check the efficiency, safety, and immunogenicity of mRNA-1273 for preventing COVID-19 up to 2 years of taking second dose of mRNA-1273. In this study, patient is given 1 intramuscular (IM) injection of 100 microgram (ug) mRNA- 1273 on Day 1 and on Day 29. The study is being carried th th out in 30000 participants from 27 July 2020 to 27 October 2020 [45].

3. Duvelisib (Copiktra), an anticancer drug, is currently being explored as treatment to reduce lung inflammation in hospitalized patients with coronavirus disease 2019 The investigators hypothesize that PI3K inhibition with Duvelisib could potentiate hyper activation of the innate immune system, polarizing macrophages, reducing pulmonary inflammation, and thereby limiting viral persistence, improving patient outcomes. A Pilot Study of Duvelisib to combat COVID 19 with 28 participants is th designed to commence on 30 September 2020 [46].

4. Decitabine can be used for Coronavirus (COVID-19) Pneumonia- Acute Respiratory Distress Syndrome (ARDS) Treatment. This nucleoside metabolic inhibitor also treats myelodysplastic syndromes (MDS). A randomized double blind placebo controlled Phase 2 trial with a 12 patient leadin to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40 patients) is carried out to assess efficacy of decitabine for treating critically ill patients with th COVID-ARDS on 29 July, 2020 [47].

5. Infliximab and Infliximab-abda are TNFα inhibitors currently FDA-approved for the treatment of autoimmune disorders, including Crohn's disease and rheumatoid arthritis. Janssen Biotech markets this chimeric monoclonal antibody. Infliximab fights against tumor necrosis factor alpha (TNF-α). The investigator have put the hypothesis that it will prevent further clinical deterioration and reduce the need for advanced cardio respiratory support and thus prevent early mortality. A Phase 2 Trial of Infliximab in Coronavirus Disease 2019 have been started in June 2020 with 17 participants [48].

6. Tramadol due to its anti-inflammatory, hypocoagulatory, antioxidant, antitussive, bactericidal, cardio-protective, analgesic and antidepressant property, can be used in COVID-19 patients. Tramadol may reduce complications in COVID-19 patients because of its antioxidant property. Not only this, tramadol also provides cardio-protective effect by lowering lactate dehydrogenase (LDH) level significantly. It is seen that in COVID-19 patients, level of T cell is highly reduced as it plays significant role in antiviral immunity. A negative correlation exists in COVID-19 patients between T cell numbers and cytokines serum level, due to which, there is increase in inflammatory cytokines, tumor necrosis factor (TNF)-α. In this condition, administration of 100 mg Tramadol every 12 hours for 10 days decreases TNF-α and increases T cell numbers. It is found that COVID-19 patients having acute respiratory failure and hypercoagulability results in thrombosis. Tramadol due to its hypocoagulable effect can be used in patients having hypercoagulable status and thromboembolic complications [49]. Apart from this, there are several drugs which are under various phases of clinical trial, their mechanism of action, dose and their marketed

Convalescent plasma therapy for COVID 19

Convalescent Plasma (CP) therapy includes administration of immunoglobulins containing plasma of a recently recovered individual from COVID 19 to any individual who is susceptible or, infected [72]. Immunized plasma binds with pathogen along with SARS-Cov 2 directly causing it to denature removing it from the peripheral blood stream. Antibody dependent cell-mediated cytotoxicity and phagocytosis also help to achieve the therapeutic effects [73]. In the present situation, human anti-SARS-CoV-2 plasma is the only therapeutic strategy that can be used to prevent and treat COVID-19. Serum IgM and IgA antibody in COVID-19 patients is detected after fifth day of onset of th symptoms whereas IgG can be detected from 14 day [74, th 75]. From 20 day, IgG can be universally detected [76]. Immunity against other betacoronaviruses lasts from 6-12 months but duration of stay of anti-SARSCoV2 antibodies in plasma is not certain [77]. So a suitable donor can donate 600 ml plasma after every 14 days for a period of 6 months. Single unit inactivation can also be done using a photosensitizer including combination of methylene blue and visible light [78] (Theraflex®), amotosalen (S-59) and ultraviolet A [79] (Intercept®); riboflavin and ultraviolet B [80] (Mirasol®). These processes do not hamper immunoglobulin activity. In 2002 it was found from a study that caprylic acid [81] and octanoic acid [82] were efficient enough to deactivate enveloped viruses. There are several plasma therapies under clinical trial whose details are mentioned in Table 3 [83-102].

Vaccines for COVID 19

Scientists throughout the world have accelerated the process to develop safe and effective COVID-19 vaccines. Vaccines aim to expose the body to an antigen and provoke an immune response that can block or kill the virus if a person becomes subsequently infected, without causing the disease. Various scientific techniques like use of virus vaccines, viral vector vaccine, nucleic acid and protein based vaccines are under development. Many vaccines have already been developed and are under clinical trial is listed in table 4 [103-117].

virus. Restrains immune disregulation in COVID 19 patients Approved for treatment of t polycythaemia vera and primary or secondary myelofibrosis as well as approved for glucocorticoid 171, is a potent and irreversible e 4). It preferentially inhibits the chymotrypsin L inhibition with carfilzomib prevents degradation of short lived misfolded and ubiquitinated proteins intended for proteasomal , azidocytidine analogue that inhibits viral reverse transcriptase, treatment of cytokine release syndrome (CRS), caused by COVID thus reducing risk of invasive mechanical ventilation and death in severely affected COVID patie able to control viral replication within 24 to 48 hours d 1 mediated nuclear import of viral proteins. The combination therapy shows better result 6. Ruxolitinib 5 mg orally every 12 hours during 14 days FDA- 2 7. Carfilzomib i.v. route 27 mg/m PR- inhibitor (1- activity CT- degradation.

8. Azvudine Oral administration of 5 tablets Antiviral of 1 mg daily effective 9. Tocilizumab i.v in two infusion 12 h apart at 8 Humanized mAb, IL mg/kg bodyweight or s.c.at 162 mg in two simultaneous doses 10. Ivermectin Ivermectin (0.2 mg /kg) (12 mg Inhibitor of SARS-CoV /weekly )+ Hydroxychloroquine 400mg/daily + azithromycin importin- α/β 500mg daily he myeloproliferative neoplasias Jakafi 55 -refractory graft-versus-host disease.

poxomycin-related proteasome Kyprolis 56, 57 -like (CT-L) - Azvudine 58 -6 receptor antagonist, approved by US FDA for Actemra 59 -19, nts.

-2 virus in vitro with a single dose of the drug Stromectol 60, 61 ue to inhibition of It is a potent, neutralizing IgG1 monoclonal antibody (mAb) effect against the spike protein of SARS and entry into human cells which neutralizes the virus responsible for Sofosbuvir is an active metabolite with high intracellular stability. SARS 2 RdRp is very likely to be effectively inhibited by sofosbuvir.

Danoprevir Hepatitis C virus NS3 protease inhibitor which selectively inhibits HCV replication. It is used in combination with ritonavir.

endothelial action that can be beneficial in COVID drug widely used in clinical oncotherapy, is a for ALI/ARDS in COVID EDP1815 is an oral formulation containing from human duodenum. Dapagliflozin is a sodium 2) inhibitor. Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA) Ravulizumab, a monoclonal antibody prevents complement destruction of cells by binding with C5, terminal complement protein. Baricitinib is licensed for treatment of rheumatoid arthritis, and has the potential to be scaled up for u It is a partial agonist of PPAR Activated Receptor gamma) causing 19 patients, angiotensin reduced, as a result angiotensin II level increases causin injury. Thus administration of TXA127, angiotensin (1 2 and thereby preventing acute kidney injury.

Pulmozyme contains an active substance calle the viscosity and quantity of airway mucus in Cystic Fibrosis (CF) patients. The similarity of mucus secretions in COVID fibrosis patients by the means of NETs makes Dornase alfa as a therapeutic option in COVID 11. LY3819253(LY- Administered intravenously CoV555) COVID-19.

12. Sofosbuvir- 400 mg Sofosbuvir and 90 mg Ledipasvir Ledipasvir, orally once daily for CoV- 14 days 13. Danoprevir+Riton Danoprevir 100 mg , one tablet avir twice a day upto 10 days.

Ritonavir 100mg, one tablet twice per day upto 10 days.

14. Sulodexide oral dose of 2 capsules each day Sulolodexide is a two for 21 days 15. Bevacizumab Bevacizumab 500mg with Anti-VEGF normal saline 100ml, iv drip promising drug ≥90min pulmonary edema.

16. EDP1815 EDP1815 twice a day for 7 Dapagliflozin days. Ambrisentan 5mg tablet Ambrisentan once daily for 14 days and 2(SGLT- Dapagliflozin 10mg tablet once a day for 14 days 17. Ravulizumab Ravulizumab IV (adjusted to Baricitinib weight, Day 1 only) Baricitinib PO OD (4mg, Days 1-14) 18. Telmisartan 80 mg Telmisartan twice daily Telmisartan has a 10- mRNA and protein level. 19. TXA127 0.5 mg/kg intravenously, for 10 In COVID- days consecutively.

of ACE- 20. Dornase alpha 2,5 mg/2 times per day for 7 days ive LY-CoV555 62 -CoV-2, thus blocking viral attachment - Harvoni 63 Roche – Adis 64 Insight -compound drug, each of them with different vessel due F 65 -19 patients.

Avastin 66 -19 through suppression of Prevotella histicola isolated Forxiga, Letairis 67 -glucose co-transporter -mediated Ultomiris, Olumiant 68 se for a pandemic.

fold higher blocking potency against angiotensin II. Micardis 69 -gamma (Peroxisome Proliferatordownregulation of AT1 receptor at -converting enzyme-2 (ACE-2) is Angiotensin-(1-7) 70 g acute kidney -7) replaces levels d dornase alpha. It reduces Pulmozyme 71 -19 and cystic -19.

12. Treatment of Patients With COVID-19 with Phase 2 June May 2022 Convalescent Plasma (COOPCOVID-19) 2020 13. Hyperimmune Convalescent Plasma in Phase 2 May 1 Sep 15 Moderate and Severe COVID-19 Disease 14. Convalescent Plasma for COVID-19 Close Phase 2 May April Contacts 2020 2021 15. Early transfusIon of Convalescent Plasma in Phase 2 May June 2021 Elderly COVID-19 Patients. to Prevent Phase 3 2020 Disease Progression. (LIFESAVER) 16. Efficacy and Safety of Early COVID- Phase 2 May 4 Aug 17 19 Convalescent Plasma in Patients Admitted for COVID-19 Infection 17. Potential Efficacy of Phase 2 April April Convalescent Plasma to Treat 2020 2021 Severe COVID-19 and Patients at High Risk of Developing Severe COVID-19 18. A Clinical Trial of Phase 2 June Feb 2021 Convalescent Plasma Compared to Best 2020 Supportive Care for Treatment of Patients With Severe COVID-19 (CAPSID) 19. Efficacy of Convalescent Plasma Therapy in Phase 3 June May 2021 Patients With COVID-19 2020 20. Assess the Safety and Efficacy of Phase 2 May Aug 2021 Convalescent Plasma to Limit COVID- 2020 19 Associated Complications 120, Brazil 1:1:1 into 3 treatment groups: A- Recruiting 94 standard (control); B- standard and convalescent plasma of 200ml volume; C- standard and convalescent plasma of 400ml volume 60, Russia 300 ml plasma on day 1 and day 2 Recruiting 95 200, New York 1 unit of approximately 200 to 250 Recruiting 96 mLvolume 182, Italy 200 ml/day for 3 days (days 1, 2, Recruiting 97 and 3).

58, India 200 ml day 1 and 2 only if Completed 98 respiratory function or COVID symptoms worsens for more than 7 days after enrolment 575, Saudi Arabia 10-15 ml/kg body weight at least Recruiting 99 once & if possible, daily, for up to 5 sessions.

106, Germany Convalescent plasma transfusion on Recruiting 100 day 1, 3 and 5.

400, India 250 ml/ day for two days from day Recruiting 101 3 of symptom onset 100, India 200 ml of ABO Recruiting 102 compatible plasma transfusion will be done

12. Immunity and Safety of Covid-19 Synthetic Phase 1 March 2020 December Minigene Vaccine Phase 2 2024 13. Safety and Immunity of Covid- Phase 1 February December 19 aAPC Vaccine 2020 2024 14. A Study to Evaluate the Safety, Phase 1 June 2020 August Reactogenicity and Immunogenicity 2021 of Vaccine CVnCoV in Healthy Adults 15. A Study to Assess Safety, Tolerability, and Phase 1 August April 2022 Immunogenicity of V591 (COVID- Phase 2 2020 19 Vaccine) in Healthy Participants (V591- 001) 100, China 5x10^6 LV-DC vaccine and Recruiting 114 1x10^8 CTLs via sub-cutaneous injections and iv infusions, respectively.

100, China Three injections of 5x10^6 each Recruiting 115 Covid-19/aAPC vaccine (artificial antigen presenting cells) via subcutaneous injections.

168, Germany Intramuscular injection by at Recruiting 116 escalating dose levels 2, 4 and 8 μg on Day 1 and Day 29.

260, Belgium 1 or 2 ascending doses of V591 Recruiting 117 will be administered via intramuscular (IM) injection.

Conclusion

From December 2019 on, the worldwide outbreak of COVID-19 has affected almost all the countries. At present, owing to its broad clinical scope, there are no clear therapeutic agents for this condition but numerous drugs, vaccines as well as human convalescent plasma have been under clinical trial throughout the world since the inception of this outbreak till date. The alarming reports of WHO for COVID 19 cases and death rates over the whole world is putting a pressing need for the development of effective drug and vaccine to control this deadly pandemic. The only FDA-approved drug is remdesivir. Many entities have shown adequate indication and promising response and thus can be a potential strategy towards this deadly disease and are under clinical trial but it will require certain time to approve and market the safe and immunogenic vaccine. The findings of good clinical trials on certain drugs and promising vaccines can prove to be boon for combating COVID-19 to narrow down the devastating effects of this global pandemic.

Conflicts of Interest

The authors declare no conflict of interest.

Author contributions

All the authors have contributed equally in designing, drafting the manuscript as per the journal submission format. All authors read and approved the final manuscript.

References

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