Remdesivir

• Remdesivir is a broad spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences.

• As of 2020 remdesivir is being tested as a specific treatment for COVID-19, and has been authorized for emergency use in the U.S. and approved for use in Japan for people with severe symptoms.

• It may shorten the time it takes to recover from the infection. Treatment is given by injection into a vein.

Mechanism of Action

• Remdesivir is a Prodrug of nucleotide that is able to diffuse into cells where it is converted to Gs-441524 mono-phosphate via the actions of esterases and phosphoramidase; this is turn is further phosphorylated to its active metabolite triphosphate by nucleoside-phosphate kinases.

• Remdesivir as an adenosine nucleotide triphosphate analog, the active metabolite of remdesivir interferes with the action of RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production.

• In respiratory syncytial viruses it causes the inhibition of RNA-dependent RNA polymerases, but prominent effect of remdesivir is to induce an irreversible chain termination.

Pharmacokinetics

• In non-human primates, the plasma half-life of the Prodrug is 20 minutes, but the activated triphosphate form has sustained intracellular levels.

Interactions

• Remdesivir is at least partially metabolized by the cytochrome P450 enzymes CYP2C8, CYP2D6.

• Blood plasma concentrations of remdesivir are expected to decrease if it is administered together with cytochrome P450 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin, primidone.

Resistance

• In non-human primates, the plasma half-life of the prodrug is 20 minutes, but the activated triphosphate form has sustained intracellular levels.

Side Effects

• The most common adverse effects in studies of remdesivir for COVID‑19 include respiratory failure and organ impairment, including low albumin, low potassium, low count of red blood cells, low count of platelets that help with clotting, and yellow discoloration of the skin.

• Other reported side effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), and infusion site reactions.

Other possible side effects of remdesivir include:

• Infusion‐related reactions. Infusion‐related reactions have been seen during a remdesivir infusion or around the time remdesivir was given. Signs and symptoms of infusion‐related reactions may include: low blood pressure, nausea, vomiting, sweating, and shivering.

• Increases in levels of liver enzymes, seen in abnormal liver blood tests. Increases in levels of liver enzymes have been seen in people who have received remdesivir, which may be a sign of inflammation or damage to cells in the liver.

Synthesis

• In this method, intermediate a is firstly prepared from L-alanine and phenyl phosphorodichloridate in presence of triethylamine and dichloromethane;

• Triple benzyl-protected ribose is oxidized by dimethyl sulfoxide with acetic anhydride and give the lactone intermediate b; pyrrolo[2,1-f] [1,2,4]triazin-4-amine is brominated, and the amine group is protected by excess trimethylsilyl chloride. n-Butyllithium undergoes a halogen-lithium exchange reaction with the bromide at −78 °C (−108 °F) to yield the intermediate c.

• The intermediate b is then added to a solution containing intermediate c dropwise. After quenching the reaction in a weakly acidic aqueous solution, a mixture of 1: 1 anomers was obtained.

• It was then reacted with an excess of trimethylsilyl cyanide in dichloromethane at −78 °C (−108 °F) for 10 minutes. Trimethylsilyl triflate was added and reacts for one additional hour, and the mixture was quenched in an aqueous sodium hydrogen carbonate. A nitrile intermediate was obtained.

• The protective group, benzyl, was then removed with boron trichloride in dichloromethane at −20 °C (−4 °F). The excess of boron trichloride was quenched in a mixture of potassium carbonate and methanol.

• A benzyl-free intermediate was obtained. The isomers were then separated via reversed-phase HPLC. The optically pure compound and intermediate a are reacted with trimethyl phosphate and methyl-imidazole to obtain a diastereomer mixture of remdesivir.

• In the end, optically pure remdesivir can be obtained through chiral resolution methods.

Potential treatment in COVID-19

• As of April 2020, remdesivir was viewed as the most promising treatment for COVID-19, and was included among four treatments under evaluation in the international Solidarity trial and European Discovery trial. The FDA stated on 1 May 2020, that it is "reasonable to believe" that known and potential benefits of remdesivir outweigh its known and potential risks, in some specific populations hospitalized with severe COVID‑19. As of May 2020, there was no good evidence that remdesivir reduced mortality in people with COVID-19.

• In January 2020, Gilead began laboratory testing of remdesivir against SARS-CoV-2, stating that remdesivir had been shown to be active against severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in animal models. On 21 January 2020, the Wuhan Institute of Virology applied for a Chinese "use patent", for treating COVID‑19.

• In a trial in China over February-March 2020, remdesivir was not effective in reducing the time for improvement from COVID‑19 or deaths, and caused various adverse effects, requiring the investigators to terminate the trial.

• In March 2020, a small trial of remdesivir in rhesus macaque monkeys with COVID‑19 infections found that it prevents disease progression. On 18 March 2020, the World Health Organization (WHO) announced the launch of a trial that would include one group treated with remdesivir. Other clinical trials are underway or planned.

• 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‑19. On 29 April 2020, based on results of the ACTT trial, the National Institute of Allergy and Infectious Diseases (NIAID) announced that remdesivir was better than a placebo in reducing time to recovery for people hospitalized with advanced COVID‑19 and lung involvement. Previously a Chinese study published in the Lancet did not show improvement. That study was subsequently criticised as underpowered. Based on the results of its study, the NIH stopped the ACTT trial and provided remdesivir to participants assigned to received placebo.

• In April 2020, the European Medicines Agency (EMA) started a 'rolling review' of data on the use of remdesivir in COVID‑19.