Remdesivir

**Remdesivir** (INN) (development code **GS-5734** is an antiviral medication developed by the American biopharmaceutical company Gilead Sciences. It is being studied during 2020 as a possible post-infection treatment for COVID-19. It is a nucleotide analog, specifically an adenosine analogue, which inserts into viral RNA chains, causing their premature termination.

## Research

Remdesivir was created and developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections. Gilead Sciences subsequently discovered that remdesivir had antiviral activity *in vitro* against multiple filo-, pneumo-, paramyxo-, and corona- viruses.

### COVID-19

See also: Coronavirus disease 2019#Research, COVID-19 drug repurposing research
In January 2020, Gilead began laboratory testing of remdesivir against SARS-CoV-2, stating that remdesivir had been shown to be active against SARS and MERS in animal models. In March 2020, a small trial of remdesivir in rhesus macaque monkeys with COVID-19 infections found that it prevents disease progression. On 21 January 2020, the Wuhan Institute of Virology applied for a Chinese "use patent", for treating COVID-19.

In late January 2020, remdesivir was given to a U.S. person with COVID-19, in Snohomish County, Washington, for "compassionate use" after he progressed to pneumonia. While no broad conclusions can be made based on the single treatment, the patient's condition improved, and he was eventually discharged. Around the same time, Chinese medical researchers reported that remdesivir seemed to have "fairly good inhibitory effects" on SARS-CoV-2, after which requests to begin clinical testing were submitted. On 6 February 2020, a clinical trial of remdesivir began in China.

On 18 March 2020 the WHO announced the launch of a four-arm pragmatic clinical trial (SOLIDARITY trial) that would include one group of patients treated with remdesivir. While a cohort study published in April 2020 saw possible improvement, determining whether or not the medication is effective is going to require a randomized controlled trial.

As of April 2020[update], remdesivir is viewed as the most promising treatment for COVID-19 by Johns Hopkins University and there are at least seven separate clinical trials underway or planned.

### Ebola virus

On 9 October 2015, the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) announced preclinical results that remdesivir had blocked the Ebola virus in Rhesus monkeys. Travis Warren, who has been a USAMRIID principal investigator since 2007, said that the "work is a result of the continuing collaboration between USAMRIID and Gilead Sciences". The "initial screening" of the "Gilead Sciences compound library to find molecules with promising antiviral activity" was performed by scientists at the Centers for Disease Control and Prevention (CDC). As a result of this work, it was recommended that remdesivir "should be further developed as a potential treatment."

Remdesivir was rapidly pushed through clinical trials due to the West African Ebola virus epidemic of 2013–2016, eventually being used in people with the disease. Preliminary results were promising; it was used in the emergency setting during the Kivu Ebola epidemic that started in 2018, along with further clinical trials, until August 2019, when Congolese health officials announced that it was significantly less effective than monoclonal antibody treatments such as mAb114 and REGN-EB3. The trials, however, established its safety profile.

## Access

On 17 March 2020, the drug was provisionally approved for use for COVID-19 patients in a serious condition in the Czech Republic. On 20 March 2020, President Trump announced that remdesivir was available for "compassionate use" by people with COVID-19; FDA Commissioner Stephen Hahn confirmed the statement at the same press conference. On 23 March 2020, Gilead voluntarily suspended access for compassionate use (excepting cases of critically ill children and pregnant women), for reasons related to supply, citing the need to continue to provide the agent for testing in clinical trials.

As of 11 April 2020, access in Canada is only to those who will be involved in a clinical trial.

## Mechanism of action and resistance

Remdesivir is a prodrug that metabolizes into its active form GS-441524. An adenosine nucleotide analog, GS-441524 interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. Though in some viruses, such as the respiratory syncytial virus but not Ebola virus, it causes the RNA-dependent RNA polymerases to pause, its predominant effect is to induce an irreversible chain termination. Unlike with many other chain terminators, this was not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to growing RNA chain.

Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance to remdesivir were identified in 2018. These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.

## Synthesis

Remdesivir can be synthesized in multiple steps from ribose derivatives. The figure to the right is one of the synthesis routes of remdesivir invented by Chun and coauthors from Gilead Sciences. 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 methylimidazole to obtain a diastereomer mixture of remdesivir. In the end, optically pure remdesivir can be obtained through chiral resolution methods.

## Other animals

Remdesivir was shown in 2019 to have possible promise for treating feline infectious peritonitis caused by a coronavirus.

It has not been evaluated or approved by the FDA for the treatment of feline coronavirus or feline infectious peritonitis but is available since 2019 through websites and social media as an unregulated black market substance as confirmed by the UC Davis School of Veterinary Medicine.