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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. GS-441524 is an adenosine nucleotide analog that 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 | pages = 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. GS-441524 is an adenosine nucleotide analog that 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, Siems 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 | pages = 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 17:12, 21 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
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 and as a treatment for Ebola virus disease and Marburg virus infections,[2] though it has subsequently also been 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]

SARS-CoV-2

In response to the 2019–20 coronavirus outbreak induced by coronavirus SARS-CoV-2, Gilead provided remdesivir for a "small number of patients" in collaboration with Chinese medical authorities for studying its effects.[19]

Gilead also started laboratory testing of remdesivir against SARS-CoV-2. Gilead stated that remdesivir was "shown to be active" against SARS and MERS in animals.[4][20]

In late January 2020, remdesivir was administered to the first US patient to be confirmed to be infected by SARS-CoV-2, in Snohomish County, Washington, for "compassionate use" after he progressed to pneumonia. While no broad conclusions were 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 stated to the media that in exploratory research considering a selection of 30 drug candidates, remdesivir and two other drugs, hydroxychloroquine and favipiravir, seemed to have "fairly good inhibitory effects" on SARS-CoV-2 at the cellular level. Requests to start clinical testing were submitted.[22][23] On February 6, 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]

On 18 March 2020, the first Italian COVID-19 patient was successfully treated with remdesivir in Genoa. The 79-year-old patient was described as "cured" by the head of the infectious diseases clinic where treatment occurred. Other patients also received the treatment.[26]

On 20 March 2020, President Trump announced remdesivir is now available for compassionate use to patients who have tested positive for COVID-19. The FDA Commissioner, Stephen Hahn, confirmed the use of remdesivir for compassionate use at the press conference along with Trump. Compassionate use is the practice of using a drug that is not approved by the FDA to treat a certain illness/condition. The non-FDA approved drug may be administered to a patient when there are no other treatment options available for that particular illness/condition.[27]

Other viruses

The active form of remdesivir, GS-441524, shows promise for treating feline coronavirus.[28]

Mechanism of action and resistance

Remdesivir is a prodrug that metabolizes into its active form GS-441524. GS-441524 is an adenosine nucleotide analog that 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.[29]

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 formula.

Remdesivir can be synthesized in multiple steps from ribose derivatives. The figure below is one of the synthesis route of remdesivir invented by Chun and coauthors from Gilead Sciences.[30] 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.
  4. ^ a b Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, et al. (June 2017). "Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses". Science Translational Medicine. 9 (396): eaal3653. doi:10.1126/scitranslmed.aal3653. PMC 5567817. PMID 28659436.
  5. ^ a b c Agostini ML, Andres EL, Siems 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.
  6. ^ Brunk, Doug. "Remdesivir Under Study as Treatment for Novel Coronavirus". Medscape. Retrieved 11 February 2020. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  7. ^ "Experimental Ebola drug 'remdesivir' may help protect against Nipah virus, say scientists". Times Now Digital. 3 June 2019.
  8. ^ The Wire Staff (2 June 2019). "Scientists Claim Drug Designed to Beat Ebola Also Fights Off Nipah". The Wire.
  9. ^ a b Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. (Washington State 2019-nCoV Case Investigation Team) (March 2020). "First Case of 2019 Novel Coronavirus in the United States". The New England Journal of Medicine. 382 (10): 929–936. doi:10.1056/NEJMoa2001191. PMID 32004427.
  10. ^ Johnson, Carolyn Y. (10 February 2020, 11:53 a.m.). "Scientists Hope an Antiviral Drug Being Tested in China Could Help Patients". The Washington Post. Retrieved 19 March 2020. {{cite news}}: Check date values in: |date= (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  11. ^ a b c d e Antiviral Compound Provides Full Protection from Ebola Virus in Nonhuman Primates (PDF). United States Army Medical Research Institute of Infectious Diseases (USAMRIID) (Report). San Diego, California. 9 October 2015. Archived from the original (PDF) on 15 March 2020. Retrieved 15 March 2020. {{cite report}}: |archive-date= / |archive-url= timestamp mismatch; 24 December 2016 suggested (help)
  12. ^ Preidt, Robert (June 29, 2017). "Experimental Drug Shows Promise Against Dangerous Viruses: Medicine worked in lab tests against germs that cause SARS and MERS infections". Archived from the original on 28 July 2017. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  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.
  15. ^ Jacobs M, Rodger A, Bell DJ, Bhagani S, Cropley I, Filipe A, et al. (July 2016). "Late Ebola virus relapse causing meningoencephalitis: a case report". Lancet. 388 (10043): 498–503. doi:10.1016/S0140-6736(16)30386-5. PMC 4967715. PMID 27209148.
  16. ^ Dwyer, Colin (27 November 2018). "Ebola Treatment Trials Launched In Democratic Republic Of The Congo Amid Outbreak". National Public Radio. Retrieved 2019-05-28. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  17. ^ McNeil, Donald G. (12 August 2019). "A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo". The New York Times. Retrieved 13 August 2019. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  18. ^ Molteni, Megan (12 August 2019). "Ebola is Now Curable. Here's How The New Treatments Work". Wired. Retrieved 13 August 2019. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  19. ^ 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)
  20. ^ Joseph, Saumya Sibi; Samuel, Maju (2020-01-31). "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)
  21. ^ Harmon, Amy (2020-02-05). "Inside the Race to Contain America's First Coronavirus Case". The New York Times. ISSN 0362-4331. Retrieved 2020-02-07. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  22. ^ Zhao, Yuning (2020-01-30). "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)
  23. ^ Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. (March 2020). "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro". Cell Research. 30 (3): 269–271. doi:10.1038/s41422-020-0282-0. PMID 32020029.
  24. ^ Grady, Denise (2020-02-06). "China Begins Testing an Antiviral Drug in Coronavirus Patients". The New York Times. ISSN 0362-4331. Retrieved 2020-02-07. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  25. ^ https://www.mzcr.cz/Soubor.ashx?souborID=40603&typ=application/pdf&nazev=Opat%C5%99en%C3%AD%20-%20LP%20Remdesivir.pdf
  26. ^ http://www.ansa.it/liguria/notizie/2020/03/17/coronavirus-a-genova-ce-primo-guarito-con-remdesivir_4e67099a-d9db-4db9-b799-08516c69b227.html
  27. ^ https://www.businessinsider.com/chloroquine-remdesivir-compassionate-use-coronavirus-what-it-means-2020-3
  28. ^ 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.
  29. ^ 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)
  30. ^ 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. 
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