In an encouraging step in the fight against COVID-19, the antiviral remdesivir is the first drug approved by the FDA for the treatment of this disease.¹ Remdesivir interferes with replication of the viral genome of RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.² It is indicated for use in adults and children 12 years of age and older weighing at least 40 kilograms (approximately 88 pounds) requiring hospitalization for COVID-19.¹ Here we discuss the metabolism of remdesivir to a nucleoside triphosphate that can be mistakenly incorporated into the genome of RNA-based viruses by the viral replication machinery, confounding the viral replication process.

Remdesivir: Metabolism and Mechanism 

Remdesivir, also known as GS-5734, is an antiviral prodrug that diffuses into cells, where it is metabolized in a multi-step process to the active nucleoside triphosphate, GS-443902.²

Intracellular metabolism of remdesivir to the active nucleoside triphosphate GS-443902, an inhibitor of the viral RNA-dependent RNA polymerase (RdRp) that interferes with viral replication. Image adapted from Eastman, et al., 2020.²

Following diffusion into cells, remdesivir is first metabolized to the intermediate alanine metabolite GS-704277, which is subsequently metabolized to the nucleoside monophosphate form.² The nucleoside monophosphate form is highly polar and cannot diffuse back out of the cell. It is converted to either the nucleoside analog GS-441524 or is phosphorylated by host cell kinases to form the active nucleoside triphosphate GS-443902. GS-443902 can then be integrated into viral RNA by the viral RNA-dependent RNA polymerase (RdRp) during replication of the viral genome, inducing delayed chain termination and inhibiting viral replication. 

Remdesivir, GS-704277, and GS-441524 have all been detected in plasma following intravenous administration of remdesivir in healthy patients, and changes in plasma levels of these three compounds have been used to study the pharmacokinetics of remdesivir.³ 

Like remdesivir, the nucleoside analog GS-441524 can also diffuse into cells and be converted to GS-443902, however GS-441524 has reduced cell permeability compared to remdesivir and the first step in the conversion of GS-441524 to GS-443902 is rate limiting.^2,4 GS-441524, along with a phosphoramidate prodrug mixture, originally emerged as a promising lead against Ebola virus, another RNA virus, in human microvascular endothelial cells.⁵ Subsequent prodrug optimization led to selection of remdesivir, one of the two isomers present in the phosphoramidate prodrug mixture, for development. Further optimization may lead to increased efficacy against the SARS-CoV-2 RdRp. 

Remdesivir is active against a variety of coronaviruses in vitro, including Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2.^2,6 It also showed therapeutic and/or prophylactic efficacy in vivo in mouse models of infection with SARS-CoV, MERS-CoV, or a mouse-adapted SARS-CoV variant encoding the SARS-CoV-2 RdRp.⁶

Remdesivir Clinical Trials Yielded Mixed Results 

In one clinical trial cited by the FDA in its approval of remdesivir, the drug shortened the median recovery time of adults hospitalized with COVID-19 who had evidence of lower respiratory tract infection by five days compared with a placebo group.^1,7 In a second, patients hospitalized with moderate COVID-19 pneumonia and receiving a five-day course of remdesivir had a statistically significant improvement in clinical status compared with patients receiving standard care.^1,8 However, in the same study, there was no statistically significant difference between patients receiving a ten-day course of remdesivir and standard care. 

While these studies are encouraging, other clinical studies were either inconclusive or showed no significant benefits associated with remdesivir. A third study cited in the FDA’s approval of remdesivir concluded that there was no statistically significant difference between a five-day and ten-day course of remdesivir in patients hospitalized with severe COVID-19.^1,9 However, this clinical trial lacked a placebo control group, making it difficult to draw conclusions about the efficacy of remdesivir. The largest controlled study, known as the Solidarity trial and conducted by the World Health Organization (WHO), concluded that, compared with a control group receiving the standard of care, remdesivir did not have a statistically significant effect on initiation of ventilation, duration of hospitalization, or mortality in adult patients hospitalized with COVID-19.^10,11 

Reviewing the mechanism of action and metabolism of remdesivir, as well as clinical trials in patients with COVID-19, reveals that there may still be a need for further optimization of this compound in order to maximize its efficacy in the fight against viral disease. Cayman offers remdesivir, as well as standards, metabolites, and derivatives that can be used in SAR studies to optimize activity against SARS-CoV-2 RdRp, as well as to study the antiviral activity, metabolism, and pharmacokinetics of this compound in vitro and in vivo.

Don’t see the remdesivir derivative you’re looking for? Contact us to learn more about Cayman’s custom synthesis and structure-based drug design services. 

Cayman also offers a variety of additional compounds to study coronaviruses. Many of these have been conveniently packaged into several focused screening libraries to simplify the identification of drugs that may be beneficial in the treatment of COVID-19 and other infectious diseases.

Cayman Compound Libraries

Anti-Inflammatory Screening Library

Antiviral Screening Library

FDA-Approved Drugs Screening Library

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References

1. FDA Approves First Treatment for COVID-19. In: fda.gov [Internet] Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19

2. Eastman, R.T., Roth, J.S., Brimacombe, K.R., et al. Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent. Sci. 6(5), 672-683 (2020).

3. Humeniuk, R., Mathias, A., Cao, H., et al. Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral for treatment of COVID-19, in healthy subjects. Clin. Transl. Sci. 13(5), 896-906 (2020).

4. Warren, T.K., Jordan, R., Lo, M.K., et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531(7594), 381-385 (2016).

5. Siegel, D., Hui, H.C., Doerffler, E., et al. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazine-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J. Med. Chem. 60(5), 1648-1661 (2017).

6. Pruijssers, A.J., George, A.S., Schäfer, A., et al. Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice. Cell Rep. 32(3), 107940 (2020).

7. Beigel, J.H., Tomashek, K.M., Dodd, L.E., et al. Remdesivir for the treatment of Covid-19 – final report. N. Engl. J. Med. (2020).

8. Spinner, C.D., Gottlieb, R.L., Criner, G.J., et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial. JAMA 324(11), 1048-1057 (2020).

9. Goldman, J.D., Lye, D.C.B., Hui, D.S., et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N. Engl. J. Med. (2020).

10. Cohen, J. and Kupferschmidt, K. The 'very, very bad look' of remdesivir, the first FDA-approved COVID-19 drug. In: sciencemag.org [Internet] Available from: https://www.sciencemag.org/news/2020/10/very-very-bad-look-remdesivir-first-fda-approved-covid-19-drug

11. WHO Solidarity trial consortium, Pan, H., Peto, R., et al. Repurposed antiviral drugs for COVID-19 – interim WHO Solidarity trial results. medRxiv (2020). [preprint]