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Added information on GS-441524 for veterinary use including statement by UC Davis/Dr. Pedersen, author of the study of GS-441524 for feline infectious peritionitis, and a recent field study of the use of GS-441524 for the elimination of coronavirus in naturally infected cats.
fixed typo, "ebolavirus" should be "ebola virus". I fixed this previously, however it was reverted by The Anome. These are two separate words.
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== Mechanism of action and resistance==
== 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 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.<ref name="Agostini_2018">{{cite journal | vauthors = Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR | display-authors = 6 | title = Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease | journal = mBio | volume = 9 | issue = 2 | date = March 2018 | pmid = 29511076 | pmc = 5844999 | doi = 10.1128/mBio.00221-18 }}</ref> However, it has been learned that the [[RNA-dependent RNA polymerase]] of ebolavirus is inhibited for the most part by delayed chain termination.<ref name="pmid30987343">{{cite journal | vauthors = Tchesnokov EP, Feng JY, Porter DP, Götte M | title = Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir | journal = Viruses | volume = 11 | issue = 4 | page = 326 | date = April 2019 | pmid = 30987343 | pmc = 6520719 | doi = 10.3390/v11040326 }}</ref>
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 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.<ref name="Agostini_2018">{{cite journal | vauthors = Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR | display-authors = 6 | title = Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease | journal = mBio | volume = 9 | issue = 2 | date = March 2018 | pmid = 29511076 | pmc = 5844999 | doi = 10.1128/mBio.00221-18 }}</ref> However, it has been learned that the [[RNA-dependent RNA polymerase]] of ebola virus is inhibited for the most part by delayed chain termination.<ref name="pmid30987343">{{cite journal | vauthors = Tchesnokov EP, Feng JY, Porter DP, Götte M | title = Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir | journal = Viruses | volume = 11 | issue = 4 | page = 326 | date = April 2019 | pmid = 30987343 | pmc = 6520719 | doi = 10.3390/v11040326 }}</ref>


Mutations in the [[mouse hepatitis virus]] [[RNA replicase]] that cause partial resistance 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.<ref name = "Agostini_2018" />
Mutations in the [[mouse hepatitis virus]] [[RNA replicase]] that cause partial resistance 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.<ref name = "Agostini_2018" />

Revision as of 18:30, 25 March 2020

Remdesivir
Clinical data
Other namesGS-5734
Routes of
administration		Intravenous
ATC code
  • None
Legal status
Legal status
Identifiers
  • (2S)-2-{(2R,3S,4R,5R)-[5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]phenoxy-(S)-phosphorylamino}propionic acid 2-ethyl-butyl ester
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.302.974 Edit this at Wikidata
Chemical and physical data
FormulaC27H35N6O8P
Molar mass602.585 g·mol−1
3D model (JSmol)
  • CCC(COC(=O)[C@@H](NP(=O)(Oc1ccccc1)OC[C@H]1O[C@@]([C@@H]([C@@H]1O)O)(C#N)c1ccc2n1ncnc2N)C)CC
  • InChI=1S/C27H35N6O8P/c1-4-18(5-2)13-38-26(36)17(3)32-42(37,41-19-9-7-6-8-10-19)39-14-21-23(34)24(35)27(15-28,40-21)22-12-11-20-25(29)30-16-31-33(20)22/h6-12,16-18,21,23-24,34-35H,4-5,13-14H2,1-3H3,(H,32,37)(H2,29,30,31)/t17-,21+,23+,24+,27-,42-/m0/s1
  • Key:RWWYLEGWBNMMLJ-YSOARWBDSA-N

Remdesivir (development code GS-5734) is a novel antiviral drug in the class of nucleotide analogs. It was developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections,[2] 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).[3][4][5] It is being studied for SARS-CoV-2 and Nipah and Hendra virus infections.[6][7][8] 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,[9] and is providing the compound to China to conduct a pair of trials in infected individuals with and without severe symptoms.[10]

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.[11] 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).[11] 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.[11] and published in the journal Nature.[2] 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.[11] The research was funded by the Defense Threat Reduction Agency and by the DoD's Medical Countermeasure Systems Joint Project Management Office.[11]

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.[12][13][14][2][15][16][17][18]

Coronavirus

See also: Coronavirus disease 2019 § Research, and COVID-19 drug repurposing research

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.[4][19] It also provided remdesivir for treatment of a "small number of patients" in collaboration with Chinese medical authorities.[20] 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,[9] and he was eventually discharged.[21] 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.[22][23] On 6 February 2020, a clinical trial of remdesivir began in China.[24]

On 17 March 2020, remdesivir was provisionally approved for use for COVID-19 patients in a serious condition in the Czech Republic.[25] 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.[26][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.[27]

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][28] 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.[29] 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 agent for testing in clinical trials.[30]

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.[31]

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 of unregulated GS-441524 developed in China was shown in a recent published study to eliminate feline coronavirus from naturally infected cats.

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 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.[5] 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 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.[5]

Synthesis

Synthesis of remdesivir in structural formulae.

Remdesivir can be synthesized in multiple steps from ribose derivatives. The figure below 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

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b c Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. (March 2016). "Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys". Nature. 531 (7594): 381–5. doi:10.1038/nature17180. PMC 5551389. PMID 26934220.
  3. ^ 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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  5. ^ 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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  13. ^ Cihlar, Tomas (20 October 2015). "Discovery and Development of GS-5734, a Novel Nucleotide Prodrug with Broad Spectrum Anti-Filovirus Activity". FANG-WHO Workshop, Fort Detrick, MD. Gilead Sciences. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  14. ^ Warren T, Jordan R, Lo M, Soloveva V, Ray A, Bannister R, et al. (Fall 2015). "Nucleotide Prodrug GS-5734 Is a Broad-Spectrum Filovirus Inhibitor That Provides Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) in Infected Non-human Primates". Open Forum Infectious Diseases. 2 (suppl 1): LB–2. doi:10.1093/ofid/ofv130.02.
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  19. ^ Joseph, Saumya Sibi; Samuel, Maju (31 January 2020). "Gilead working with China to test Ebola drug as new coronavirus treatment". Thomson Reuters. Archived from the original on 2020-01-31. Retrieved 2020-01-31. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  20. ^ Taylor, Nick Paul (24 January 2020). "Gilead mulls repositioning failed Ebola drug in China virus". Fierce Biotech. Retrieved 31 January 2020. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  21. ^ Harmon, Amy (5 February 2020). "Inside the Race to Contain America's First Coronavirus Case". The New York Times. ISSN 0362-4331. Retrieved 7 February 2020. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  22. ^ Zhao, Yuning (30 January 2020). "Three drugs fairly effective on novel coronavirus at cellular level". China News Service. Archived from the original on 2020-01-29. Retrieved 2020-02-01. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
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  25. ^ "Data" (PDF). www.mzcr.cz. Retrieved 2020-03-24.
  26. ^ "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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  31. ^ Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H (April 2019). "Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis". Journal of Feline Medicine and Surgery. 21 (4): 271–281. doi:10.1177/1098612X19825701. PMC 6435921. PMID 30755068.
  32. ^ Tchesnokov EP, Feng JY, Porter DP, Götte M (April 2019). "Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir". Viruses. 11 (4): 326. doi:10.3390/v11040326. PMC 6520719. PMID 30987343.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  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. 
  • "Remdesivir". Drug Information Portal. U.S. National Library of Medicine.
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