Commentary - (2021) Volume 18, Issue 2
Aman Kapoor1, Amardeep Ankalgi1, Upasana Thakur1, M.S. Ashawat1 and Rohit Bhatia2*
1Department of Pharmaceutical Analysis, Laureate Institute of Pharmacy Kathog, Jawalaji, Himachal Pradesh, India
2Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab-142001, India
Received Date: July 13, 2020; Accepted Date: January 20, 2021; Published Date: January 27, 2021
SARS-CoV-2 has been emerged from Wuhan in China and has now shacked out more than 200 Countries and territories all over the world. World’s best scientists are contributing and endeavouring to find drugs, immuno-modulators and vaccines for the treatment of COVID-19. SARS-CoV-2 virus is a betacoronavirus and positive-stranded RNA virus that originates from the Coronaviridae family. The most important structural proteins of SARS-CoV-2 are spike trimeric (S) protein, membrane (M) protein, envelop (E) protein and the nucleocapsid (N) protein. The SARS-CoV-2 begins its life cycle, when the S protein binds with the host cells receptor ACE2 (angiotensin-converting enzyme 2). The viral protein(M) and genome (Protein-N) RNA eventually get assembled into virions (with Protein-S and HE), Endoplasmic reticulum and Golgi apparatus. According to the various research reports, there aremore than 50 drugs, immunomodulators and vaccines that may be effective against COVID-19. Some drugs had shown the in vitro activity against MERS-CoV, SARS-CoV and SARS-CoV-2. The aim of this review is to highlight the properties,structure, life cycle of SARS-CoV-2 and description of the agents which show potential efficacy against SARS-CoV-2.
SARS-CoV-2; Immune-modulator; ACE2; RNA; MERS-CoV
COVID-19 is Zoonotic disease [1] which is caused by severe acute respiratory syndrome causing coronavirus-2(SARS-CoV-2) [2,3], and spreads from animals to human [4]. SARS-CoV-2 has been emerged from Wuhan in China and has now shake out 199 Countries and territories all over the world [5]. It was first reported to the WHO on December 31st, 2019 and WHO declared the COVID-19 outbreak a global health emergency on January 30, 2020. As on 9th July 2020, a total of 12,162,626 confirmed cases of COVID-19 and551,974 deaths have been reported all around the world. The Global death rate is 15% and Global recovery rate is 45.33%[6].All over the world, best scientists are contributing and carrying out immense research to find drugs,immuno-modulators or vaccines for the treatment of COVID-19.
The coronavirus belongs to the family of virus that causesrespiratory tract infections including breathing difficulty, tiredness, fever, dry cough and lung infection [7]. The SARS-CoV- 2 virus is a beta, positive-stranded RNA virus that originates from the Coronaviridae family. Other viruses from the same family include the SARS-CoV and MERS-CoV which appeared in 2002 and 2016 [8].The name coronavirus springs from the Latin word corona which means crown or aureole (Figure 1), which refers to the characteristic look resembling a crown or a solar corona around the virus when viewed under TEM, due to the surface covering of virus with club-shaped protein spikes [9].
Figure 1: SARS-CoV-2 image under TEM.
The most important structural proteins of SARS-CoV-2 are spike trimeric (S) protein, membrane (M) protein, envelop (E) protein and the nucleocapsid (N) protein (Figure 2). The family of corona viruses also have hemagglutinin esterase (HE) glycoprotein[10].The RNA genome consists of seven other genes that are maintainedin the order: ORF1a, ORF1b, S, OEF3, E, M, N in 5' to 3' direction. The maximum part of the RNA genome is secured by the ORF1a/b, which generate the two viral replicase proteins that are polyproteins (PP1a and PP1ab) [11]. These two polyproteins are further producing the sixteen mature nonstructural proteins (NSPs) which help in the formation of the replicase transcriptase complex. The rest of the genome encodes the mRNA, which helps in the formation of important structural proteins, i.e., spike, envelope, membrane, nucleocapsid and other essential proteins [11]. Some strains of HE protein produces envelop-associated proteinin the corona virus [12]. The RNA genome of Corona viruses is first packed in the nucleocapsid protein and then covered with envelope [13].
Figure 2: Structure of SARS-CoV-2.
The SARS-CoV-2 begins its life cycle,when the S Protein binds to the host cells receptor ACE2 (angiotensin-converting enzyme 2) [13].After the binding to the receptor, there is conformational change in the S protein which helps in ease of the viral envelope fusion with the host cell membrane, incorporated via an endosomal pathway [14]. Then SARS-CoV-2 releases the viral RNA in the host cell [15,16]. Then polyprotein gets cleaved into sixteen mature non-structural proteins (NSPs) which help in the formation of the replicase transcriptase complex and then finally translated into suitable viral proteins [17]. The viral protein(M) and genome( Protein-N) RNA eventually assembled into virions (with Protein-S and HE) in the Endoplasmic reticulum and Golgi apparatus, which are budding into the lumen of the ER-Golgi intermediate compartment.In the finalstep it transportsvia vesicles and released out of the cell [18] (Figure 3).
Figure 3: The life cycle of SARS-CoV-2.
COVID-19 is a viral infection which spread rapidly.The FDA,WHO,biotech industry, pharmaceutical companies and research organisations such as the National Institutes of Health (NIH) of US,is working together for developing the new vaccines and find the new drugs for the treatment of COVID-19 [19]. According to the scientists, there are 50 drugs, immune-modulators and vaccines that may be effective against COVID-19. Some of these vaccines, immune-modulators or drugs have been under clinical trials and showing better result against COVID-19. Some of investigational Drugs (Table 1), Immuno-modulators (Table 2) and Vaccines (Table 3) are described below which have revealed the in vitro activity against MARS-CoV, SARS-CoV, and SARS-CoV-2.
| S.No. | Drug Name | Drug class | Mechanism | Rationale use | Reference |
|---|---|---|---|---|---|
| 1 | Hydroxychloroquine and chloroquine | Anti-rheumatoid arthritis and Antimalaria Drug | Inhibition of viral enzymes, viral glycosylation, virus assembly transport, and virus release. | In-vitro activity against SARS-CoV-2 and may have immune-modulating properties | [21,22,23,24] |
| 2 | Favipiravir | Antiviral drug | RNA-dependent RNA polymerase (RdRp) inhibitor | Showing the activity against the SARS-CoV-2 | [25,26,27] |
| 3 | Remdesivir | Antiviral Drug | Inhibits viral replication through premature termination of RNA transcription | In vitro activity against SARS-CoV-2 at low micromolar concentrations and has a high selectivity index. | [28,29,30,31,32] |
| 4 | Lopinavir/ritonavir | Anti-HIV Drug | Protease inhibitors | Anti-SARS-CoV activity, in-vitro and in clinical studies | [33,34,35] |
| 5 | Ribavirin | Antiviral Drug | An adenosine analog that acts as an inhibitor of RNA-dependent RNA polymerases (RdRps) | Reduce the risk of acute respiratory distress syndrome (ARDS) in late-stage patients | [28,34,36,42] |
| 6 | IFN-α | Antiviral activity | First-line innate immune defence of the body against having antiviral activity | IFN-α2b spray can adequately reduce the infection rate of respiratory syncytial virus and tnSARS-CoV | [37,38,39] |
| 7 | Arbidol | Antiviral drug | Inhibits cell entry of enveloped viruses by blocking viral fusion with host cell membrane. | arbidol can effectively inhibit COVID-19 at a low concentration. | [40,41] |
Table 1: Investigational drugs for the treatment of covid-19.
| S.No. | Therapy | Industry Name | Mechanism | Description | Ref. |
|---|---|---|---|---|---|
| 1. | Remestemcel-L | Mesoblast Ltd | Immunomodulatory , target on MSC. |
Allogeneic mesenchymal stem cell (MSC) product candidate being investigated as a treatment for ARDS associated with COVID-19. | [43] |
| 2. | Ifenprodil (NP-120;) | Algernon Pharmaceuticals | N-methyl-d-aspartate(NDMA) receptor glutamate receptor antagonist | NMDA is linked to inflammation and lung injury. An injectable and long-acting oral product are under production to begin clinical trials for COVID-19 and acute lung injury. | [44] |
| 3. | Technosphere, powder Inhaled therapy | MannKind and Immix Ltd | Powders dissolve rapidly with moist lung surface, and release drug quickly to systemic exposure. | Dry powder inhaled formulation with potential to treat ARDS caused by COVID-19. | [45] |
| 4. | Gimsilumab | Roivant Ltd | Monoclonal antibody that targets GM-CSF | A pro-inflammatory cytokine that is up-regulated in patients with COVID-19. | [46] |
| 5. | Brilacidin | Innovation Pharmaceuticals | Defensin- mimetic that mimics the immune system and distort the pathogen membrane and kill the cell. | Still under clinical-stage testing at a US regional biocontainment laboratory. | [47] |
| 6. | TJM2 | I-MAB Biopharma | TJM2 is a neutralizing antibody against (GM-CSF), | TJM2 is a neutralizing antibody against human granulocyte-macrophage colony stimulating factor (GM-CSF), an important cytokine that plays a critical role in acute and chronic inflammation. | [48] |
| 7. | (LEAPS) peptide technology | CEL-SCI Corporation | Immunotherapy which stimulates protective cell mediated T cell responses and reduce viral load | Ligand antigen epitope presentation system (LEAPS) peptide technology to reduce COVID-19 viral load and successive lung damage. | [49] |
| 8. | TAK-888 | Takeda Pharmaceutical Company | They focus on Concentrated virus-specific antibodies. | Concentrated virus-specific antibodies from plasma collected from people who have already recovered from COVID-19. | [51] |
| 9. | Vascular leakage therapy | Q BioMed Partner Mannin Research | Reduction of endothelial dysfunction | Targets the angiopoietin-Tie2 signaling pathway to reduce endothelial dysfunction. | [53] |
| 10. | Vir and NIH, Antibody-directed therapy | Vir Biotechnology and NIH. | Human monoclonal antibodies | mAbs against coronaviruses | [50] |
| 11. | Antibody-Eli lilly & Abcella | Eli Lilly and AbCellera | Develops antibody which act as immune-modulater | Treatment from more than 500 unique antibodies isolated from one of the first US patients to recover from COVID-19. | [52] |
Table 2: Immunomodulators under investigation for the treatment of covid-19.
| S.No. | Vaccine | Pharmaceutical Industry |
Description | Reference |
|---|---|---|---|---|
| 1. | BNT162 mRNA vaccine |
BioNTech and Pfizer Ltd. | BioNTech and Pfizer Ltd developed mRNA-based vaccine and start Phase 1 trial. | [54] |
| 2. | S-Trimer vaccine |
GlaxoSmithKline [GSK] and Clover Biopharmaceuticals | Preclinical trials are underway using GSK’s adjuvants and Clover’s proprietary proteins, which boost the immune system. | [55] |
| 3. | INO-4800 vaccine | Inovio Pharmaceuticals | Human clinical (Phase 1) trials began in 15 April 2020. In addition, Inovio made smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery. | [56] |
| 4. | TNX-1800 vaccine | Tonix Pharmaceuticals | The vaccine is a modified horsepox virus. | [57] |
| 5. | Intranasal COVID-19 vaccine | Altimmune, Inc. | Finally developed the vaccine and start the preclinical trial on animal. | [58] |
| 6. | Saponin-based Matrix-M adjuvant vaccine | Novavax, Inc. | Phase I clinical trial expected to initiate in late spring of 2020. Vaccine boosts the immune response. | [59] |
| 7. | Johnson & Johnson. SARS-CoV-2 vaccine | Johnson & Johnson Collaboration with U.S. Department of Health & Human. | BARDA (Biomedical advanced Research and Development Authority) will provide funding accelerated development of a vaccine candidate into Phase 1 clinical studies. | [60] |
| 8. | mRNA-1273 vaccine | Moderna, Inc. | A clinical phase study has been initiated in 45 COVID-19 patients on 16 March 2020 at Kaiser Permanente Washington Health Research Instituted in Seattle. | [61] |
| 9. | Brilacidin adjuvant vaccine | Innovation Pharmaceuticals | Evaluated the potential antiviral properties as a defending adjuvant and activate the primary innate antiviral immune response. | [62] |
| 10. | PCR-based DNA vaccine | Applied DNA Sciences and Takis Biotech Ltd. | Preclinical development of a LinearDNA Covid-19 vaccine | [63] |
Table 3: Vaccines under investigation for treatment of covid-19.
Chloroquine & Hydroxychloroquine
Hydroxychloroquine and chloroquine, both are orally active drugs. Chloroquine has been used for malaria treatment, connective tissue diseases and chemoprophylaxis. Hydroxychloroquine is used for treatment of rheumatoid arthritis, porphyria cutanea tarda and systemic lupus erythematosus. Both drugs have shown in vitro activity against MARS-CoV, SARS-CoV, and SARSCoV- 2, where hydroxychloroquine having higher potency against SARS-CoV-2 [20-23]. On 19 March 2020, the President of the United States, Donald Trump, announced that chloroquine and hydroxychloroquine/Plaquenil were approved by the USFDA(Food and Drug Administration) to be tested as a treatment for COVID-19 [24].Chloroquine and hydroxychloroquine is being tested in various clinical trials conducted by academic institutions and government agencies.
Favipiravir
Favipiravir is an antiviral drug which is RNA-dependent RNA polymerase (RdRp) inhibitor. It also have anti-influenza virus activity and ability to block the replication of flavi-, noro-, alpha-, bunya-, arena- and other RNA viruses [25].After entering into the cell, Favipiravir gest converted into an active phosphoribosylated form (favipiravir-RTP) which are easily identified as a substrate by viral RNA polymerase,then get attached to the RNA polymerase and inhibits them [26]. The National Medical Products Administration of China has approved the use of Favipiraviras a treatment for COVID-19. According to the clinical report, which was tested on 70 patients, the drug has shown efficacy in treating the disease with minimal side effects. The clinical trial is being conducted in Shenzhen, Guangdong province in china [27].
Remdesivir
Remdesivir is an investigational intravenous drug with a broad-spectrum antiviral action that inhibits viral replication through premature termination of RNA transcription [28]. Remdesivir is having antiviral activity against single stranded RNA viruses such as Junin virus, Nipah virus, respiratory syncytial virus, Lassa fever virus, Hendra virus, and the coronaviruses (including MERS and SARS viruses) [29,30].In vivo testing on mice specified that remdesivir can effectively reduce the viral load in lung tissue of mice infected with MERS-CoV. Remdesivir also helps to improve lung function and diminish pathological damage to lung tissue [31]. Wang et al. found that remdesivir is a potent drug having in vitro activity against SARS-CoV-2 at low micromolar concentrations and has a high selectivity index (half-maximal effective concentration (EC50), 0.77 μM; half-cytotoxic concentration (CC50) > 100 μM; SI > 129.87) [28]. Holshue et al. reported that remdesivir revealed in vitro activity against SARS-CoV- 2 and related beta-coronaviruses and yielded promising results in the treatment of patients with COVID-19 in the United States [32].
Lopinavir/Ritonavir
Lopinavir/ritonavir is a protease inhibitor which is used in combination with other medications to treat adults and children over 14 days of age who are infected with HIV-1[33]. Chu et al. found that lopinavir/ ritonavir has anti-SARS-CoV activity in vitro and in clinical studies[34].Lopinavir-ritonavir did not show promising result for treatment of COVID-19 patients with pneumonia in a recent clinical trial in China[35],but still under investigation in a WHO and USFDA study.
Ribavirin
Ribavirin is a mono-phosphoramidate prodrug of remdesivirtriphosphate (RDV-TP), which is an antiviral drug containingnucleoside analogue that acts as an inhibitor of RNA-dependent RNA polymerases (RdRps) [32].Ribavirinis also used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers[36]. According to the clinical research report, the combined therapy of ribavirin with ritonavir/lopinavir had reduced the risk of acute respiratory distress syndrome (ARDS) in late-stage patients infected with the coronavirus [28,34].
IFN-α
IFN is the first-line innate immune defence of the body against viral activity [37]. IFN-α is a broad-spectrum antiviral candidate that is mainly used in the treatment of hepatitis. Clinical study revealed that recombinant human IFN-α2b spray can adequately reduce the infection rate of respiratory syncytial virus, adenovirus,influenza virus and tnSARS-CoV [37,38].IFN-α atomization can be utilized as a choice of treatment for COVID-19 [39].
Arbidol
Arbidol is an antiviral that can be used to treat influenza virus [40]. According to the clinical study report arbidol can effectively inhibit COVID-19 at a low concentration [41-64].
COVID-19 outbreak has spread all around the world and matter of great worry is thatthere are presently no drugs and vaccines finally approved by the U.S. food and Drug Administration (FDA) can be used as a therapeutic candidate against COVID-19. Although many approved drugs has been repurposed for the potential treatment of COVID-19 and many are under clinical trials. Many Govt., semi-Govt., private industries, research labs and academicians are working day and night in order to develop the possible treatment of COVID-19.
