Discovery Technologies: The Story of Remdesivir
Effective treatment options for the COVID-19 virus emerged from both currently marketed therapeutics, as well as from drugs in investigational discovery for the treatment of similar infectious diseases. The antiviral drug Remdesivir, under evaluation as an antiviral drug, was originally evaluated for the treatment of Ebola virus disease in 2014. In vitro Remdesivir studies highlighted its ability to disrupt viral replication and demonstrated its broad-spectrum antiviral activity against other pathogenic RNA viruses, including coronaviruses. Remdesivir is an ATP analog that competes with ATP for incorporation into RNA, decreasing overall viral RNA production.
The initial discovery of Remdesivir’s antiviral potential was the result of collaborative research by Gilead Sciences, the U.S. Centers for Disease Control and Prevention (CDC), and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), with the goal of identifying potential therapeutic agents for disease caused by RNA-based viruses.
The research team discovered that a 1’-cyano-substituted adenine C-nucleoside ribose analogue (Nuc) along with its prodrug form were highly potent against RNA viruses including Ebola, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS).
Activation of the prodrug exhibited slow kinetics, therefore alterations were made to allow for higher rates of pharmacologically active NTP in cells. Applying LC-MS/MS detection technology the molecules were analyzed for efficiency of prodrug activation.The most effective pro-drug was GC-5734 – or remdesivir as it’s called today – which was then tested for its antiviral activity against Ebola and various other viruses, using the PerkinElmer Opera Phenix™ High-Content Screening System. Further testing to evaluate antiviral activity with technologies such as EBOV GFP-reporter viruses using plate reader measurements, ATP-based measurements of viral cytotoxicity on the EnVision plate reader, or quantifying viral load of infected cells using the automated ScicloneG3 liquid handling station for qRT-PCR, helped to provide supportive context to the effectiveness of Remdesivir as an antiviral therapeutic. To evaluate pharmacokinetics, metabolism, and distribution, in vivo primate studies were performed. These experiments collectively illustrated that once-daily dosing of Remdesivir at 10 mg/kg provides sustained intracellular drug metabolite levels even in sanctuary tissues where viruses may persist. Efficacy studies assessing survival rates confirmed an increase in antiviral effects in doses of minimally 10 mg/kg.
This data suggests Remdesivir is a potent and selective inhibitor of Ebola viral infection and was presented as the first case of substantive post-exposure protection against the Ebola virus. The U.S. Food and Drug Administration issued an Emergency Use Authorization that allows Remdesivir to be used to treat hospitalized adult and pediatric patients with COVID-19.
With clinical trials ongoing, Remdesivir remains a focal point in antiviral research. At PerkinElmer, providing researchers with the best solutions possible for the development of novel antiviral treatments remains a primary focus.