REMDESIVIR: A promising antiviral candidate drug for the COVID-19 pandemic


Abbreviations

1. RdRP-dRP- RNA-dependent RNA polymerase

2. COVID-19- coronavirus disease 2019

3. SARS-CoV- severe acute respiratory syndrome coronavirus

4. ICTV - International Committee on Taxonomy of Viruses

5. HAE cultures - Human airway epithelial cultures


Objective

Remdesivir is a viral RNA-dependent RNA polymerase (RdRP) inhibitor, it binds to the viral RdRP and inhibits viral replication through premature termination of RNA transcription.. It is used to treat variety of virus infections.

  • Name: Remdesivir (GS-5734)

  • Routes of administration : Intravenous

  • Trade name : Veklury

  • Molecular Formula : C27-H35-N6-O8-P

  • Molecular Weight: 602.5815 g·mol−1


Introduction

The coronavirus disease 2019 (COVID-19) coronavirus pneumonia epidemic, which began in December 2019 has developed into a global pandemic and all populations are generally susceptible to infection with this highly contagious virus. Because of there is a significant increase in infected people, the need for the development of vaccines for the treatment and prevention of COVID-19 is become very important for the field of medicine and research and development (R&D). Genetics studies on new covid virus show that there is 79.5% similarity between the COVID virus and SARS-CoV. New coronavirus and SARS-CoV share 94.6% similarity in the amino acid sequences of seven conserved non-structural proteins. The International Committee on Taxonomy of Viruses (ICTV) has found that the new coronavirus belongs to the “severe acute respiratory syndrome-related coronavirus” species and named the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Mechanism

Remdesivir is an RdRP inhibitor that can achieve antiviral result by inhibiting viral nucleic acid synthesis. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus and the genomic replication process of RNA viruses is dominated by RdRP which is encoded by the virus itself. The protein synthesis system of the host cell will use the viral genomic RNA as template for the synthesis of RdRP after the virus invades the host cell. After the synthesis of RdRP it will help with the transcriptional synthesis of negative strand of subgenomic RNA and replication of viral genomic RNA into the host cell. RdRP will synthesize thousands of nucleotides and facilitates other biological activities after the virus invades the host cell. RdRP is an effective target of many antiviral and anticorona virus drugs. Most of the anti-coronavirus drugs are nucleotide analogues or RNA interferons. Remdesivir has potent antiviral activities against a variety of RNA viruses such as Coronaviridae, Filoviridae, Paramyxoviridae and Arenaviridae in cultured cell lines and nonhuman primate models. The antiviral activity of remdesivir is selective and has no significant effect on DNA viruses and certain RNA viruses (such as alphaviruses and retroviruses).



1. Coronaviridae

It is a family of positive strand RNA viruses which has its genetic material protected by envelope. Coronavirus is a subfamily of coronaviridae. They are associated with a variety of diseases in humans and vertebrates and can cause respiratory, digestive, circulatory and nervous system diseases. Coronaviruses exhibit family-wide genetic diversity in RdRP and can be inhibited by rendesivir, current research has demonstrated that. Remdesivir has broad-spectrum antiviral drug functions. It can be used against SARS-CoV-2, MERS-CoV, SARS-CoV, human coronavirus OC43 (HCoV-OC43), human coronavirus 229E (HCoV-229E), murine hepatitis virus (MHV) and porcine deltacoronavirus (PDCoV).


1.1. SARS-CoV-2

The antiviral activities of remdesivir against SARS-CoV-2 in vitro. In Vero E6 cells, remdesivir effectively blocked SARS-CoV-2 infection at low concentrations (EC50 = 0.77 μM) and exhibited low cytotoxicity (CC50 > 100 μM) and a high selection index (SI > 129.87). In addition, remdesivir has 1.76μM EC90 value against SARS-CoV-2 in Vero E6 cells the antiviral potential of remdesivir against SARS-CoV-2 in both Vero E6 and human airway epithelial (HAE) models. The results show that post infection treatment with remdesivir exerts a very strong antiviral effect.


To evaluate the effect of remdesivie in a rhesus macaque model of SARS-CoV-2 infection on COVID-19 outcome. Animals treated with remdesivir did not show any signs of respiratory disease and showed reduced pulmonary infiltrates on radiographs compared to vehicle-treated animals. In the bronchoalveolar lavages there is significant reduction was observed in virus titres as 12 h after the first treatment was administered. At necropsy, the lung viral loads of the remdesivir-treated animals on day 7 after inoculation were significantly lower and reduction in lung tissue damage was also observed. In summary,it shows a clear clinical benefit in SARS-CoV-2-infected rhesus macaques treatment with remdesivir initiated early during infection. These data support that to prevent the progression to severe pneumonia remdesivir treatment for COVID-19 patients is a helpful therapeutic tool.


1.2. SARS-CoV

SARS-CoV is an infectious disease-causing pathogen. It is responsible for causing severe respiratory disease in humans. The activity of remdesivir against SARS-CoV in primary HAE cells found approximately 0.069 μM. In addition, the administration of remdesivir 24 h after SARS-CoV infection also resulted in decreased viral titres of SARS-CoV at 48 and 72 h post inoculation and there is not any measurable cellular toxicity observed in the HAE cultures. In a mouse model of SARS-CoV pathogenesis, the prophylactic and early therapeutic administration of remdesivir significantly reduced the lung viral load, improved respiratory function, including bronchiolitis, perivascular inflammatory infiltration.


CONCLUSION

Remdesivir is a nucleotide analog prodrug responsible for inhibition of SARS-CoV-2 RdRP. Remdesivir shown to be play an important role in shortening the time of recovery in adults who are infected with COVID-19 and is also helpful in lowering the Respiratory tract infections. It has been authorized as an emergency drug for patients with COVID-19 in several countries including India. However, to confirm the effect of remdesivir for treating COVID-19 patients a large-scale of clinical trials should be conducted. Remdesivir has also shown some adverse effects on peoples such as respiratory failure, gastrointestinal distress, low albumin and potassium levels, low count of red blood cells.

Aakanksha Shukla

Dept. of Biochemistry and Biotechnology

St. Xavier's College, Ahmedabad


REFERENCES:


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3. Voluntary Licensing Agreements for Remdesivir. [Last accessed on 2020 May 20]. Available from: https://wwwgileadcom/purpose/advancing-global-health/covid-19/voluntary-licensing-agreements-for-remdesivir.


4. FDA Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Remdesivir (gs-5734tm)[Last accessed on 2020 May 20]. Available from: https://wwwfdagov/media/137566/download.


5. Image Source: Google images







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