27th October 2020
Remdesivir

Everything that you should know about Remdesivir (Origin, Mode of Action, and Effect on Covid-19)

Remdesivir is quite trending around the internet as one of the highly searched potential therapy against Novel SARS-CoV2,  the coronavirus which is responsible for COVID-19 disease. Remdesivir is an “adenosine triphosphate analogue” which was first coined in the literature in 2016. As every person has a bit of an idea about DNA knows about its four basic components i.e., adenosine, guanine, thymine, and cytosine. Remdesivir is just an analogue (mimic) of adenosine.  Remdesivir was mentioned in an article published by Sheahan et al in 2017, that Remdesivir possesses activity against the family of coronavirus. Remdesivir is also being researched as a potential treatment to SARS-CoV2 by De et al.,2020 and the work has been published in PNAS.

To have a clear idea about Remdesivir we need to know more about adenosine which is a nucleotide. A nucleoside is made of a sugar moiety and a nucleobase, on the other hand, a nucleotide is composed of a sugar a nucleobase, and at least one phosphate or phosphate-like group. Nucleosides and nucleotides both play vital roles in the process of replication and transcription of genetic information.  Some nucleotide and nucleoside analogue has been utilized in several studies conducted by De Clercq, in different years from 1992 till 2012 and they published in various journals that since decades nucleotide analogues are used in chemotherapeutic treatments, antiparasitic, antibacterial or antiviral therapeutics.

Nucleobase

Ideally, a nucleoside or a nucleotide analogue mimics the structure of a natural nucleoside/tide with very minor changes. These minor changes still keep it enough to be recognized as a normal nucleotide by viral or cellular enzymes. Due to misunderstanding of the viral cell this analogue gets incorporated into the DNA or RNA replication cycle. The modifications in the analogues leads to the and/or termination or disruption of replication in the virus. Thus the duplication of the virus may come to an end.

Despite the earlier attacks of SARS in 2003 and MERS in 2012, but still, the earlier clinical trials of coronavirus-specific antivirals do not have pretty much information which may effectively work against SARS-CoV2.  Currently, the major focus is on most of the compounds with a broad spectrum of antiviral activities. Several of these compounds being extensively researched are taken under consideration for randomized controlled clinical trials, and one strong candidate is thought to be Remdesivir (RDV, formerly GS-5734) on the basis of earlier demonstrations.

Now let’s see what type of nucleotide analogue is Remdesivir

Remdesivir is a phosphoramidite prodrug having  1’-cyano-substituted nucleotide analogue. Its RDV-TP that is a triphosphate form of Remdesivir resembles adenosine triphosphate that is ATP, which we all know about.  RDV-TP can be used as a substrate of viral RdRp which is an RNA-dependent RNA polymerase enzyme. 1′-cyano analogue generated by Gilead displayed the broadest spectrum of antiviral activity against several viruses such as HCV, yellow fever virus (YFV), dengue-2 virus (DENV-2), influenza A, parainfluenza 3, Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus (SARS-CoV), with the best antiviral activity against EBOV.

cyano-analogue

Pro-Drung-Portion-of-the-molecule

This analogue was shown to have a broader spectrum of antiviral activity both in vitro and in vivo studies against non-segmented negative-sense  RNA viruses of the Filoviridae such as Ebola virus (EBOV) and Paramyxoviridae such as Nipah virus (NiV) families.   This analogue has also shown in vitro activity against viruses in the Pneumoviridae group such as respiratory syncytial virus (RSV) family. A broad-spectrum of antiviral activity of this analogue has been noticed against coronaviruses including SARS-CoV and MERS-CoV evident from both in vitro and animals models.  All these results together unify to describe a  refined mechanism of Remdesivir-mediated RNA synthesis inhibition in coronaviruses as a nucleotide analogue which can be direct-acting antiviral (DAA)  according to JBC.

Mode of Action

As we are now aware that Remdesivir is a nucleotide analogue (mimic) that can be used as an alternative nucleotide. When a cell encounters or gets infected by SARS-CoV2, The spike protein on its surface known as the S protein recognizes the  ACE2 receptor and binds to it which then allows the invagination of the virus along with cell membrane (endosome).

Endosome fuses with a lysosome and the process of endocytosis lead to the unraveling of the viral RNA.  This RNA is the genetic code of SARS-CoV 2 which is positive-sense single-stranded RNA virus. The viral RNA utilizes the host’s translational machinery such as ribosomes to translate itself to synthesize proteins such as RNA dependent RNA polymerase (RDRP).  RDRB makes multiple copies of viral RNA by polymerization; on the other hand, the viral RNA also translates to synthesize other viral proteins such as S protein and viral envelope for producing a completely new virus.

Remdesivir is a prodrug which is an inactive form of the medication, and after administration into the body, it metabolizes into an active form such as G-441524.  RDRP misunderstands G-441524 or other Remdesivir as normal adenosine and adds G-441524 as adenosine in the places of normal adenosine and a defective viral RNA is thus produced which is unable to perform like original viral RNA. G-441524 is also seen to overcome the activity of 3’-5’ exonuclease activity (ExoN) of the virus.

ExoN is able to make corrections in the defective viral RNA but interestingly a high dose of Remdesivir overcomes ExoN activity. Eventually, Remdesivir reduces the viral RNA load and an increased Remdesivir overcomes ExoN activity leading to a further decrease in Viral RNA load.

There are possibilities that viruses may undergo such mutation which may generate a strict proofreading ability, In such a situation this type of analogue such as Remdesivir may not be useful any further, because every defect inserted will be proofread more strictly and quickly than previously. Well, in the current scenario Remdesivir seems to be a somewhat potential drug against SARS-CoV2.

Remdesivir-BioTrivia

Remdesivir is an Intra Venously administered drug Manufactured by Gilead, to act as an inhibitor of RNA synthesis. It has a few adverse effects such as nausea, vomiting, and transaminitis. The study published on April 29 in the Lancet has this information for us that the patients receiving Remdesivir had clinical improvement, numerically faster than those receiving placebo (the drug lookalike but made of inactive substance) among patients who showed the symptoms for the duration of 10 days or less. Unfortunately, this improvement effect was not statistically significant and that means it is not completely reliable to be used on patients.  The treatment with Remdesivir was stopped soon because of its adverse effect in 18 (12%) patients as compared to the four (5%) patients who stopped placebo early.

Conclusively, this  Lancet study inferred that Remdesivir was not associated with statistically significant clinical benefits in adult patients admitted to hospital due to severe COVID-19. The time to clinical improvement in Covid-19 patients was definitely noticed to be reduced by Remdisivir. Other studies had different results and different perspectives on Remdisivir.

A study published in journals under the American Society of Microbiology inferred that GS-5734 (another form of Remdesivir) impairs fitness and virulence of SARS-CoV. This study concludes to supporting further research and development of GS-5734 as a potential therapeutic against coronavirus.

A study Funded by Gilead Sciences published in The New England Journal of Medicine conducted studies on a cohort of patients hospitalized with Covid-19 was treated with compassionate-use Remdesivir.  Clinical improvement was observed in 36 patients out of 53. It also suggested that a better Measurement of efficacy is required and more randomized, placebo-controlled trials of Remdesivir therapy is a necessity.

Finally, a study conducted by Wang et al., 2020 published in Cell Research has shown enough positive attitude towards Remdisiver confidentially suggested that  Remdesivir should be assessed in human patients suffering from the novel coronavirus disease. Their findings revealed that Remdesivir is highly effective in controlling Sars-Cov2 infection in vitro. Their perspective is to view Remdesivir as a  compound that has been used earlier in human patients with quite a good safety track record and has shown to be effective against various ailments caused by other viruses. Together we have accepted that Remdesivir maybe possibly be one the effective drug against Covid-19.

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