Remdesivir is a broad-spectrum antiviral drug developed by United States-based pharmaceutical company Gilead Sciences initially against the hepatitis C virus and respiratory syncytial virus. Further research also investigated possible applications against the Ebola virus
, SARS coronavirus, and MERS coronavirus
The drug never reached the approval stage for use against the viruses mentioned above, either due to the emergence of more potent therapeutic approaches or because the public health threat from the involved virus became negligible.
However, due to the coronavirus pandemic caused by the SARS-CoV-2 virus
, researchers identified old and existing antiviral medications as possible treatment options. Remdesivir has been fast-tracked as a candidate drug against COVID-19, as well as one of the major treatment options under the International Solidarity trial and the European Discovery Trial.
Remdesivir Explained: Concept and Pharmacology
Basic Concept as a Prodrug
Understanding how remdesivir works against certain viruses
and its potential against novel viruses from spillover events
requires understanding the fundamental concept behind its development, as well as its uses, effects, and mode of action or pharmacology.
Take note that it is not an actual active drug but a prodrug. A prodrug is a compound that serves as a forerunner of an actual drug. Once administered, the body converts it into a pharmacologically active drug through metabolism.
In the case of remdesivir, it diffuses into cells once administered, where it is metabolized into an active metabolite called GS-441524. This metabolite is converted or metabolized further into an adenosine nucleotide triphosphate form called a nucleoside.
A nucleotide is one of the structural components of DNA or RNA, while a nucleoside is similar to a nucleotide minus a phosphate group. Moreover, adenosine is a multifunctional compound that forms when adenine, one of the five primary genetic units of the genetic code, attaches to a sugar-based structure called a ribose.
Mechanism of Action
The specific nucleoside emerging from remdesivir is an analogue that resembles a genetic structural component—an altered version of adenosine. Upon the administration and metabolism of this drug, the virus incorporates this nucleoside analogue by accident in its growing RNA strands while it attempts to replicate inside a host cell.
Once incorporated into the RNA of the virus, the nucleoside analogue confers a biological feature that hinders the further expansion of the RNA strand, thereby rendering the virus unable to replicate. Remdesivir fundamentally prevents viral replication.
There are two more characteristics the make remdesivir work against viruses. First, its metabolism also results in the incorporation of a carbon-nitrogen group in the growing RNA strand. This group distorts the shape of the strand and hinders its further growth.
Second, the metabolite of the drug has a structural feature involving a carbon-carbon chemical bond rather than a nitrogen-carbon bond found in natural adenosine. The altered chemical bond prevents the nucleoside analogous from being recognized and clipped from the viral RNA.
FURTHER READINGS AND REFERENCES
- Gordon, C. J., Tchesnokov, E. P., Woolner, E., Perry, J. K., Feng, J. Y., Porter, D. P., & Götte, M. 2020. “Remdesivir is a Direct-Acting Antiviral that Inhibits RNA-Dependent RNA Polymerase from Severe Acute Respiratory Syndrome Coronavirus 2 with High Potency.” Journal of Biological Chemistry. 295(20): 6785–6797. DOI: 1074/jbc.ra120.013679
- Gordon, C. J., Tchesnokov, E. P., Feng, J. Y., Porter, D. P., and Götte, M. 2020. “The Antiviral Compound Remdesivir Potently Inhibits RNA-Dependent RNA Polymerase from Middle East Respiratory Syndrome Coronavirus.” Journal of Biological Chemistry. 295(15): 4773–4779. DOI: 1074/jbc.ac120.013056
- Kupferschmidt, K. and Cohen, J. 2020. “WHO Launches Global Megatrial of the Four Most Promising Coronavirus Treatments. Science.” Science. DOI: 1126/science.abb8497
- 2020. “Launch of a European Clinical Trial Against COVID-19.” Inserm Press Office. Inserm. Available online
- Tchesnokov, E., Feng, J., Porter, D., & Götte, M. 2019. “Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir.” Viruses. 11(4): 326. DOI: 3390/v11040326