Remdesivir is an adenosine nucleotide analog that has a wide-spectrum of antiviral activity both in vitro and in vivo in animal models against Ebola virus, SARS, Marburg virus and, MERS.
In vitro testing done by Gilead pharmaceutical, Remdesivir demonstrated its activity against SARS CoV-2. The safety and efficacy in the treatment of COVID-19 are being evaluated in multiple ongoing Phase 3 clinical trials.
The drug is produced by Gilead pharmaceutical company.
Remdesivir is a prodrug of GS-441524. This means that it has to be activated to an active form known as GS-441524 for it to work.
Specifically Remdesivir is an adenosine analog. It therefore mimics the activity of adenosine but it isnt a true adenosine. An adenosine nucleoside analog, GS-441524 interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production
Adenosine is a nucleotide base without a phosphate group. Nucleotide bases are building blocks in the synthesis of nucleic acids such as Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
Uses of Remdesivir
Remdesivir was used in the treatment of Ebola but it wasn’t effective
It was also used in the treatment of Marbug virus.
Articles recommended for you:
Remdesivir is administered parenterally via an intravenous route.
Intravenous infusions in phase I clinical trials have shown a good safety and pharmacokinetic properties.
Nausea and vomiting which are the most common side effects.
Other side effects associated with Remdesivir are respiratory failure, hypoalbuminemia, hypokalemia (low potassium), anemia, low platelet count and jaundice (Yellow skin discoloration).
Mechanism of action of Remdesivir
From the published articles, it is shown that its activity is mediated by a viral polymerase and proofreader exoribonuclease.
For clear understanding of how the drug works, it is important to remember how the virus gets into the body and its replication cycle.
The coronavirus has a surface protein known as Spike protein or S protein. The receptor binding domain (RBD) of S protein on the surface of SARS-CoV-2 binds to the Angiotensin converting enzyme -2 (ACE2) receptor on the cell surface to facilitate the virus get into the host cell;
Once in the cell, the virus exposes its RNA material and translates its RNA replicase, to forms an RNA replicase-transcriptase complex.
This viral genome then hijacks the host cell machinery mainly the ribosomes and starts to translate and make viral proteins for itself with the help of an enzyme known as RNA dependent RNA polymerase.
Through the process of transcription and replication, the complex forms RNA negative strands that will be translated for the structural proteins of the virus later.
Then the viral structural proteins and viral RNA material in the cytoplasm assemble into new viral particles, which are released from infected cells by exocytosis to infect other cells.
Coronavirus is a single stranded positive sense RNA virus meaning it has a single RNA strand and has to use an enzyme to generate a complementary DNA strand.
Remdesivir works by inhibiting viral RNA production in such a way that, by acting as an adenosine analog, it confuses the virus to pick it up and incorporate it into its RNA structure instead of the real adenosine base and eventually causing a defective viral RNA making the RNA dependent RNA polymerase enzyme to stop working. Through this mechanism it inhibits viral RNA synthesis.
Once remdesivir is added into the growing chain at the i position, it does not cause an immediate stop but it will continue to extend three more nucleotides down to stop the strand at the i + 3 position.
The virus has a viral protein known as 3’5’ exoribonuclease (ExoN). This protein works as a proofreader detecting any problem within the viral RNA strand and fixing it.
This protein has the ability to repair the already damaged RNA strand by Remdesivir reducing its efficacy.
A mutation in 3’5’ exoribonuclease (proofreader) may confer coronavirus ie SARS CoV-2 resistance to Remdesivir.
Remdesivir is at partially metabolized by the cytochrome P450 enzymes (CYP2C8, CYP2D6, and CYP3A4).
Blood plasma concentrations of remdesivir are may to decrease if it is given together with cytochrome P450 inducers like, carbamazepine, phenytoin, phenobarbital, and Rifampicin.
Research on activity of Remdesivir on coronaviruses
Remdesivir is now authorised for emergency use for the treatment of hospitalised patients with severe COVID-19 disease.
The optimal duration of treatment is still being studied in ongoing clinical trials. Under the EUA, both 5-day and 10-day treatment durations are suggested, based on the severity of disease.