Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses

Amirian and Levy have recently collected the knowledge on remdesivir and its nucleoside analog [1]. This overview can be interesting for the readers of Cyclodextrin News as remdesivir formulated by sulfobutyl beta-cyclodextrin is on clinical trials against Covid-19 infections in several countries.

Remdesivir (GS-5734, Fig. 1a) is an investigational broad-spectrum small-molecule antiviral drug that has demonstrated activity against RNA viruses in several families, including Coronaviridae (such as SARS-CoV, MERS-CoV, and strains of bat coronaviruses capable of infecting human respiratory epithelial cells), Paramyxoviridae (such as Nipah virus, respiratory syncytial virus, and Hendra virus), and Filoviridae (such as Ebola virus). Originally developed to treat Ebola virus infection, remdesivir is a prodrug of the parent adenosine analog, GS-441524 (Fig. 1b), both of which are metabolized into an active nucleoside triphosphate (NTP) by the host (Fig. 1c). The parent nucleoside, GS-441524, has displayed antiviral activity against SARS-CoV, Marburg virus, and feline infectious peritonitis virus, among others.

Fig. 1. Chemical structures of: a) Remdesivir; b) GS-441524; c) triphosphate metabolite of both drugs

Remdesivir mechanism of action

As a nucleoside analog, remdesivir acts as an RdRp inhibitor, targeting the viral genome replication process. The RdRp is the protein complex CoVs use to replicate their RNA-based genomes. After the host metabolizes remdesivir into active NTP, the metabolite competes with adenosine triphosphate (ATP; the natural nucleotide normally used in this process) for incorporation into the nascent RNA strand. The incorporation of this substitute into the new strand results in premature termination of RNA synthesis, halting the growth of the RNA strand after a few more nucleotides are added.

In vivo studies: animal models & veterinary studies

Animal studies on remdesivir efficacy against CoVs using transgenic mice and rhesus macaques showed that both prophylactic and therapeutic remdesivir had protective effects against MERS-CoV replication and associated pathology, generally resulting in less lung damage and better pulmonary function compared to controls.

Some veterinary studies have also examined the effects of the parent nucleoside, GS-441524, in cats with Feline infectious peritonitis (FIP) , a condition associated with very high mortality in cats. The results indicated that GS-441524 (and presumably, its prodrug remdesivir) is also a promising therapeutic candidate for treatment of alphacoronavirus-related disease in cats.

Clinical trials

Results of the clinical trials currently underway in the U.S. and China will provide crucial information about whether remdesivir represents a viable treatment option for COVID-19. If the trial findings are ultimately positive, it will be imperative to ensure that the drug is produced on a commercial scale capable of meeting the demand generated by both the current pandemic and future outbreaks.

 
[1] E. Susan Amirian,  Julie K. Levy (2020) Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health 9, 100128
https://doi.org/10.1016/j.onehlt.2020.100128