In the course of SARS-CoV-2 infection, molecular mechanism concerning the viral attachment to the overall process of viral dissemination in the host during the replication cycle plays a vital role. Hence, these molecular mechanisms need to be identified early to alleviate and inhibit the viral transmission and viability in susceptible hosts. Potential therapeutic approach against SARS-CoV-2 can be effectively achieved by the following ways (Tay et al 2020):
a) Inhibition of spike protein by antiviral agent
b) Antibodies to spike protein
c) Protease inhibitor
d) Development of memory T cells
e) Neutralization of pro-inflammatory cytokines
a) Inhibition of spike protein by antiviral agent
b) Antibodies to spike protein
c) Protease inhibitor
d) Development of memory T cells
e) Neutralization of pro-inflammatory cytokines
A brief description of the aforementioned ways is given here below.
a) Inhibition of spike protein by the antiviral agent:
The process of blocking the entry of the virus is the foremost way to be away from the infection of the SARS-CoV-2. Either development of an anti-viral agent targeting the spike glycoprotein or antibodies against it plays a vital role in preventing the infection.
The spike protein binds with the host cells expressing a specific receptor called angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 spike protein (S) contains two subunits viz. S1 and S2. SARS-CoV-2 harbor a special S1/S2 furin recognizable site that is absent in other beta-B coronaviruses. In addition to furin precleavage, the cellular serine protease TMPRSS2 is also required to process the SARS-CoV-2 spike protein before viral entry to the host cell.
The interaction of heptad repeat 1 (HR1) and 2 (HR2) domains in the S2 subunit forms a six-helix bundle (6-HB) present in between fusion peptide (FP) and transmembrane domain (TM) followed by the cytoplasmic domain (CP). This 6-HB configuration is highly conserved in dangerous coronaviruses except for the coronaviruses exhibiting milder symptoms (such as 229E and NL63) in which the length of HR2 helix differs. Mutated residues of amino acids present in the HR1 domain are considered to be associated with enhanced interaction with the HR2 domain.
Recently, Xia et al (2020) reported a lipopeptide derived from EK1 called EK1C4 (formed by conjugating cholesterol molecule with EK1 peptide). This lipo-peptide could be used for the prevention and treatment of prevailing SARS-CoV-2 infection. EK1C4 is a potent fusion inhibitor against the fusion of viral membrane with the host cells mediated by spike (S) protein. EK1 targets the HR1 domain and inhibits fusion in due course of establishing infection by the virus. The research was evident with the inhibition of 5 live human coronaviruses (HCoVs) including SARS-CoV. For instance, the intranasal application of EK1C4 in mice protected them from HCoV-OC43 infection (Xia et al 2020). Thus, the development of antiviral agents the spike protein can be one way to suppress infection of SARS-CoV-2.
b) Antibodies to spike protein:
The antibodies developed against the spike protein either raised by vaccination or by adoptive transfer (transfer of immune cell into the patient) could block SARS-CoV-2 during its interaction to host cell receptor ACE2. Neutralizing antibodies to spike protein begin to develop by the second week of infection and the majority of patients develop the neutralizing antibody by the third week (Temperton et al 2005 and CGTN 2020). Besides, the use of convalescent serum samples has good clinical results in COVID-19 (Xinhua 2020). These sera do have the antibodies against the COVID-19 infection for neutralization of virus (meaning blocking of virus infection by antibodies).
Moderna company from the US with the National Institute of Allergy and Infectious Diseases (NIAID) has been working together on the candidate vaccine for COVID-19 called mRNA-1273. NIAID is a part of the National Institutes of Health (NIH). The study on mRNA-1273 started on January 13 with the final sequencing of mRNA-1273 and Moderna has announced Phase-1 data on May 18, 2020 (Moderna 2020). According to NIAID, mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a prefusion stabilized spike (S) protein of SARS-CoV-2 (ClinicalTrials.gov)(Figure 1).
Likewise, in April 2020, the University of Oxford has begun testing a COVID-19 vaccine called ChAdOx1 nCoV-19 for human trials. ChAdOx1 has been made from a virus called ChAdOx1. This virus is a weakened version of the common cold virus i.e. Adenovirus responsible to cause infections in Chimpanzees. However, the virus has been genetically modified so that it cannot replicate in humans. With genetic modification, the spike glycoprotein (S) from the COVID-19 virus has been inserted into the virus so that the body may recognize the virus and develop an immune response to the Spike protein preventing the pathway following subsequent infection (University of Oxford 2020). The clinical trial is still continuing to date and in case of being inefficient, the programme will be stopped.
The process of blocking the entry of the virus is the foremost way to be away from the infection of the SARS-CoV-2. Either development of an anti-viral agent targeting the spike glycoprotein or antibodies against it plays a vital role in preventing the infection.
The spike protein binds with the host cells expressing a specific receptor called angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 spike protein (S) contains two subunits viz. S1 and S2. SARS-CoV-2 harbor a special S1/S2 furin recognizable site that is absent in other beta-B coronaviruses. In addition to furin precleavage, the cellular serine protease TMPRSS2 is also required to process the SARS-CoV-2 spike protein before viral entry to the host cell.
The interaction of heptad repeat 1 (HR1) and 2 (HR2) domains in the S2 subunit forms a six-helix bundle (6-HB) present in between fusion peptide (FP) and transmembrane domain (TM) followed by the cytoplasmic domain (CP). This 6-HB configuration is highly conserved in dangerous coronaviruses except for the coronaviruses exhibiting milder symptoms (such as 229E and NL63) in which the length of HR2 helix differs. Mutated residues of amino acids present in the HR1 domain are considered to be associated with enhanced interaction with the HR2 domain.
Recently, Xia et al (2020) reported a lipopeptide derived from EK1 called EK1C4 (formed by conjugating cholesterol molecule with EK1 peptide). This lipo-peptide could be used for the prevention and treatment of prevailing SARS-CoV-2 infection. EK1C4 is a potent fusion inhibitor against the fusion of viral membrane with the host cells mediated by spike (S) protein. EK1 targets the HR1 domain and inhibits fusion in due course of establishing infection by the virus. The research was evident with the inhibition of 5 live human coronaviruses (HCoVs) including SARS-CoV. For instance, the intranasal application of EK1C4 in mice protected them from HCoV-OC43 infection (Xia et al 2020). Thus, the development of antiviral agents the spike protein can be one way to suppress infection of SARS-CoV-2.
b) Antibodies to spike protein:
The antibodies developed against the spike protein either raised by vaccination or by adoptive transfer (transfer of immune cell into the patient) could block SARS-CoV-2 during its interaction to host cell receptor ACE2. Neutralizing antibodies to spike protein begin to develop by the second week of infection and the majority of patients develop the neutralizing antibody by the third week (Temperton et al 2005 and CGTN 2020). Besides, the use of convalescent serum samples has good clinical results in COVID-19 (Xinhua 2020). These sera do have the antibodies against the COVID-19 infection for neutralization of virus (meaning blocking of virus infection by antibodies).
Moderna company from the US with the National Institute of Allergy and Infectious Diseases (NIAID) has been working together on the candidate vaccine for COVID-19 called mRNA-1273. NIAID is a part of the National Institutes of Health (NIH). The study on mRNA-1273 started on January 13 with the final sequencing of mRNA-1273 and Moderna has announced Phase-1 data on May 18, 2020 (Moderna 2020). According to NIAID, mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a prefusion stabilized spike (S) protein of SARS-CoV-2 (ClinicalTrials.gov)(Figure 1).
 |
Figure 1. Illustration showing development of mRNA vaccine for SARS-CoV-2(Concept inspired from Moderna and illustration created from BioRender app) |
c) Protease inhibitor:
Protease inhibitor especially the serine protease TRMPSS2 can prevent the cleavage of the spike protein. This protease is essential for viral fusion into the host cell.
d) Development of memory T cells:
Virus-specific memory CD8+ T cells generated from previous infection or vaccination can differentiate into effector cells during secondary infection. Whenever such cells identify infected cells presenting virus-specific epitopes (portions of antigens recognized by antibodies), they degranulate and kill infected cells prior to the development of mature virions.
e) Neutralization of pro-inflammatory cytokines:
In adverse immunological reaction, degranulation of virus-infected cells provokes pro-inflammatory cytokines resulting in the symptoms of the cytokine storm. Elevated levels of cytokines (such as TNF) can cause septic shock and failure of multiple organs. Some of the patients are reported to have myocardial damage and circulatory failure (Ruan et al 2020). The trapping of these pro-inflammatory cytokines through customized columns offers a novel treatment method.
REFERENCES:
| Tay, M.Z., Poh, C.M., Rénia, L. et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0311-8 |
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| Xia, S., Liu, M., Wang, C. et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res 30, 343–355 (2020). https://doi.org/10.1038/s41422-020-0305-x |
| Ruan, Q., Yang, K., Wang, W., Jiang, L. & Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. https://doi.org/10.1007/s00134-020-05991- x (2020). |
| Temperton, N. J. et al. Longitudinally profiling neutralizing antibody response to SARS coronavirus with pseudotypes. Emerg. Infect. Dis. 11, 411–416 (2005). |
| CGTN. Expert: recovered coronavirus patients are still prone to reinfection. YouTube https://www.youtube. com/watch?v=GZ99J7mlaIQ (2020). |
| Xinhua. China puts 245 COVID-19 patients on convalescent plasma therapy. Xinhuanet http://www. xinhuanet.com/english/2020-02/28/c_138828177. htm (2020). |
| https://www.modernatx.com/modernas-work-potential-vaccine-against-covid-19 |
| http://www.ox.ac.uk/news/2020-04-23-oxford-covid-19-vaccine-begins-human-trial-stage |
| https://clinicaltrials.gov/ct2/show/NCT04283461 |
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