Remdesivir is a broad-spectrum antiviral drug developed by the Gilead Sciences1. It was originally developed to treat hepatitis C and was then tested against Ebola virus and Marburg virus, but was ineffective as per studies.
In January 2020, Gilead tested remdesivir against SARS-CoV-2 and observed very good results against severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in animal models2. Early data from a controlled trial carried out by the U.S. National Institutes of Health, suggests that remdesivir is effective in reducing the recovery time from 15 to 11 days in people seriously ill with COVID-193. Based on the results, it has been authorized for emergency use in the U.S. and approved for use in Japan for people with severe symptoms4.
Remdesivir active metabolite, adenosine nucleoside triphosphate analog, interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production5. For the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2 arrest of RNA synthesis occurs after incorporation of three additional nucleotides. Hence, remdesivir is classified as a direct-acting antiviral agent that works as a delayed chain terminator6.
Remdesivir drug has 6 chiral centres and its synthesis involves around 23 to 25 steps, starts from the basic raw materials, L-alanine and pyrrolo[2,1-f] [1,2,4]triazin-4-amine by using 65 to 70 different raw materials and reagents, which includes the usage of dangerous chemical Trimethyl silyl cyanide. To get optically pure required isomer (Remdisivr), either need to purify the mixture of isomers by prep HPLC or need to follow chiral resolution method.
The presence of organic impurities or solvents, in the trace amounts may influence the efficacy and safety of drug. To check and confirm the presence of them in the drug, we need to have all the possible Remdesivir impurities. Based on the published literature, around 35 to 40 impurities and metabolites are available. All the impurities/ metabolites have chiral centres and should be optically pure form, the synthesis and characterization of them is a challenging task with the available limited literature and time.