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Remdesivir

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Remdesivir
Remdesivir.svg
Clinical data
Other namesGS-5734
Routes of
administration
Intravenous
ATC code
  • None
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
FormulaC27H35N6O8P
Molar mass602.585 g·mol−1
3D model (JSmol)

Remdesivir (development code GS-5734) is a novel antiviral drug in the class of nucleotide analogs. Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and causes their pre-mature termination. It was developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections,[1] though it subsequently was found to show antiviral activity against other single stranded RNA viruses such as respiratory syncytial virus, Junin virus, Lassa fever virus, Nipah virus, Hendra virus, and the coronaviruses (including MERS and SARS viruses).[2][3][4] It is being studied for SARS-CoV-2 and Henipavirus infections.[5][6][7] Based on success against other coronavirus infections, Gilead provided remdesivir to physicians who treated an American patient in Snohomish County, Washington in 2020, who was infected with SARS-CoV-2,[8] and is providing the compound to China to conduct a pair of trials in infected individuals with and without severe symptoms.[9]

Background

On 9 October 2015, the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) announced encouraging preclinical results that the GS-5734 compound had blocked the Ebola virus in Rhesus monkeys. The West African Ebola virus epidemic lasted from 2013 to 2016. Travis Warren, who has been USAMRIID's principal investigator since 2007, said that the "work is a result of the continuing collaboration between USAMRIID and Gilead Sciences.[10] 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).[10] As a result of this work, it was recommended that GS-5734 "should be further developed as a potential treatment." Their findings were presented at the annual Infectious Diseases Society of America's (IDSA) IDWeek conference held at the San Diego Convention Center from 7 to 11 October.[10] and published in the journal Nature.[1] The Ebola research was conducted in the Department of Defense's Biosafety Level 4 maximum containment USAMRIID laboratories, the only DoD organization with maximum Level 4 capabilities.[10] The research was funded by the Defense Threat Reduction Agency and by the DoD's Medical Countermeasure Systems Joint Project Management Office.[10]

Research usage

Laboratory tests suggest remdesivir is effective against a wide range of viruses, including SARS-CoV and MERS-CoV. The medication was pushed to treat the West African Ebola virus epidemic of 2013–2016.

Ebola virus

Remdesivir was rapidly pushed through clinical trials due to the West African Ebola virus epidemic of 2013–2016, eventually being used in at least one human patient despite its early development stage at the time. Preliminary results were promising and 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.[11][12][13][1][14][15][16][17]

COVID-19

In late January 2020, in response to the 2019–20 coronavirus pandemic, 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 of CoV infection.[3][18] It also provided remdesivir for treatment of a "small number of patients" in collaboration with Chinese medical authorities.[19] Also in late January 2020, remdesivir was administered to the first U.S. patient confirmed to be infected by SARS-CoV-2, 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 dramatically the next day,[8] and he was eventually discharged.[20] Also in late January 2020, Chinese medical researchers reported that remdesivir and two other drugs, hydroxychloroquine and favipiravir, seemed to have "fairly good inhibitory effects" on SARS-CoV-2 (after exploratory research that examined 30 drug candidates), after which requests to begin clinical testing were submitted.[21][22] On 6 February 2020, a clinical trial of remdesivir began in China.[23]

On 17 March 2020, remdesivir was provisionally approved for use for COVID-19 patients in a serious condition in the Czech Republic.[24] While no broad conclusions can be made based on the single treatment, results of remdesivir treatment of an Italian COVID-19 patient in Genoa, a 79-year-old, were described as successful on 18 March 2020. Other patients also received the treatment, the results of which are not known.[25][verification needed] On that date, the WHO announced the launch of a large four-arm pragmatic clinical trial (SOLIDARITY trial) that includes one group of patients treated with remdesivir.[26]

On 20 March 2020, it was announced that Cleveland, Ohio-based University Hospitals would run two clinical trials to test the effectiveness of remdesivir against coronavirus.[clarification needed][27] On the same date, President Trump announced that remdesivir was now available for "compassionate use" by patients that had tested positive for COVID-19; FDA Commissioner Stephen Hahn confirmed the statement at the same press conference.[28] That decision allowed physicians of COVID-19 patients to request permission to use the unapproved drug in the context of remdesivir's investigational new drug (IND) status, outside of participation in a formal clinical trial.[citation needed]

On 23 March 2020, Gilead suspended access to remdesivir 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.[29]

Veterinary applications

The active form of remdesivir, GS-441524, was shown in 2019 to have possible promise for treating feline infectious peritonitis caused by a coronavirus.[30]

GS-441524 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 Dr. NielsC. Pedersen, DVM PhD, School of Veterinary Medicine, UC Davis. A pill form was shown in to eliminate feline coronavirus from naturally infected cats.[31]

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. It was unknown whether it terminates RNA chains or causes mutations in them.[4] However, it has been learned that the RNA-dependent RNA polymerase of ebola virus is inhibited for the most part by delayed chain termination.[32]

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.[4]

Synthesis

Synthesis of remdesivir in structural formulae.

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.[33] 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 an additional 1-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.

See also

References

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  2. ^ Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, et al. (March 2017). "GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses". Scientific Reports. 7 (1): 43395. Bibcode:2017NatSR...743395L. doi:10.1038/srep43395. PMC 5338263. PMID 28262699.
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  4. ^ a b c Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. (March 2018). "Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease". mBio. 9 (2). doi:10.1128/mBio.00221-18. PMC 5844999. PMID 29511076.
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  24. ^ "Data" (PDF). www.mzcr.cz. Retrieved 2020-03-24.
  25. ^ "Coronavirus: a Genova c'è primo guarito con Remdesivir - Liguria" [Coronavirus: The first cured with Remdesivir in Genoa]. Agenzia ANSA (in Italian). 17 March 2020.
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  33. ^ US 9724360, Chun BK, Clarke MO, Doerffler E, Hui HC, Jordan R, Mackman RL, Parrish JP, Ray AS, Siegel D, "Methods for treating Filoviridae virus infections", issued 19 July 2017, assigned to Gilead Sciences Inc. 

External links

  • "Remdesivir". Drug Information Portal. U.S. National Library of Medicine.