Remdesivir

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Remdesivir
GS-5734 structure.png
Clinical data
Other namesGS-5734
Legal status
Legal status
Identifiers
CAS Number
ChemSpider
KEGG
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. It was developed by Gilead as a treatment for Ebola virus disease and Marburg virus infections,[1] 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 coronaviruses (including MERS and SARS viruses).[2][3] It is being studied for 2019-nCoV and Nipah and Hendra virus infections.[4][5][6] Based on success against other coronavirus infections, Gilead provided remdesivir to physicians that treated an American patient in Snohomish County, Washington infected with 2019-nCoV, and is providing the compound to China, to conduct a pair of trials in infected individuals with and without severe symptoms.[7]

Research usage[edit]

Laboratory tests suggests 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. Although it turned out to be safe, it was not particularly effective against Ebola.

Ebola virus[edit]

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.[8][9][10][11][12][13][14][15]

2019 novel coronavirus[edit]

In response to the 2019–20 Wuhan coronavirus outbreak induced by coronavirus 2019-nCoV, Gilead provided remdesivir for a "small number of patients" in collaboration with Chinese medical authorities for studying its effects.[16] Gilead also started laboratory testing of remdesivir against 2019-nCoV. Gilead stated that remdesivir was "shown to be active" against SARS and MERS in animals.[17]

In late January 2020, remdesivir was administered to the first US patient to be confirmed to be infected by 2019-nCoV, 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,[18] and he was eventually discharged.[19] Also in late January 2020, Chinese medical researchers stated to the media that in exploratory research considering a selection of 30 drug candidates, three of them, remdesivir, chloroquine and lopinavir/ritonavir, seemed to have "fairly good inhibitory effects" on 2019-nCoV at the cellular level. Requests to start clinical testing were submitted,[20][21] and on February 6, 2020 a clinical trial of remdesivir began in China.[22]

Other viruses[edit]

The active form of remdesivir, GS-441524, shows promise for treating Feline coronavirus.[23]

Mechanism of action and resistance[edit]

Remdesivir is a prodrug that metabolizes into its active form GS-441524. GS-441524 is an adenosine nucleotide analog that confuses viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. It is unknown whether it terminates RNA chains or causes mutations in them.[24]

Mutations in the mouse hepatitis virus RNA replicase that causes 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.[24]

See also[edit]

References[edit]

  1. ^ 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. Bibcode:2016Natur.531..381W. doi:10.1038/nature17180. PMC 5551389. PMID 26934220.
  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.
  3. ^ 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.
  4. ^ "Remdesivir Under Study as Treatment for Novel Coronavirus". Medscape. Retrieved 11 February 2020.
  5. ^ "Experimental Ebola drug 'remdesivir' may help protect against Nipah virus, say scientists". Times Now Digital. 3 June 2019.
  6. ^ "Scientists Claim Drug Designed to Beat Ebola Also Fights Off Nipah". The Wire. 2 June 2019.
  7. ^ Johnson, Carolyn (10 February 2020). "10:53 a.m. Scientists Hope an Antiviral Drug Being Tested in China Could Help Patients". The New York Times. Retrieved 10 February 2020.
  8. ^ Preidt R (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.
  9. ^ Cihlar T (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.
  10. ^ 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 Infect Dis. 2. doi:10.1093/ofid/ofv130.02.
  11. ^ 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. Bibcode:2016Natur.531..381W. doi:10.1038/nature17180. PMC 5551389. PMID 26934220.
  12. ^ 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.
  13. ^ "Ebola Treatment Trials Launched In Democratic Republic Of The Congo Amid Outbreak". NPR.org. Retrieved 2019-05-28.
  14. ^ McNeil DG (12 August 2019). "A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo". The New York Times. Retrieved 13 August 2019.
  15. ^ Molteni M (12 August 2019). "Ebola is Now Curable. Here's How The New Treatments Work". Wired. Retrieved 13 August 2019.
  16. ^ "Gilead mulls repositioning failed Ebola drug in China virus". Fierce Biotech. Retrieved 31 January 2020.
  17. ^ Joseph SS, Samuel M (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.
  18. ^ Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. (January 2020). "First Case of 2019 Novel Coronavirus in the United States". The New England Journal of Medicine. 0. doi:10.1056/NEJMoa2001191. PMID 32004427.
  19. ^ Harmon A (2020-02-05). "Inside the Race to Contain America's First Coronavirus Case". The New York Times. ISSN 0362-4331. Retrieved 2020-02-07.
  20. ^ Zhao Y (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.
  21. ^ Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. (February 2020). "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro". Cell Research. doi:10.1038/s41422-020-0282-0. PMID 32020029.
  22. ^ Grady D (2020-02-06). "China Begins Testing an Antiviral Drug in Coronavirus Patients". The New York Times. ISSN 0362-4331. Retrieved 2020-02-07.
  23. ^ 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.
  24. ^ a b 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.