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Remdesivir Remdesivir (Development Code GS-5734) Is a Novel Antiviral Remdesivir Drug in the Class of Nucleotide Analogs

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Remdesivir Remdesivir (Development Code GS-5734) Is a Novel Antiviral Remdesivir Drug in the Class of Nucleotide Analogs Remdesivir Remdesivir (development code GS-5734) is a novel antiviral Remdesivir 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 the Wuhan coronavirus, 2019- Clinical data nCoV, and is providing the compound gratis, to China, to Other GS-5734 conduct a pair of trials in infected individuals with and without names severe symptoms.[7] Legal status Legal status US: Investigational New Drug Contents Identifiers Research usage IUPAC name Ebola virus (2S)-2-{(2R,3S,4R,5R)-[5-(4-Aminopyrrolo[2,1- Novel coronavirus (2019-nCoV) f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy Other viruses -tetrahydro-furan-2-ylmethoxy]phenoxy-(S Mechanism of action and resistance )-phosphorylamino}propionic acid 2-ethyl- See also butyl ester References CAS 1809249-37-3 (http://w Number ww.commonchemistry. org/ChemicalDetail.asp Research usage x?ref=1809249-37-3) Laboratory tests suggests remdesivir is effective against a wide ChemSpider 58827832 (http://www. range of viruses, including SARS-CoV and MERS-CoV. The chemspider.com/Chem medication was pushed to treat the West African Ebola virus ical-Structure.5882783 epidemic of 2013–2016. Although it turned out to be safe, it was 2.html) not particularly effective against Ebola. KEGG D11472 (http://www.ke gg.jp/entry/D11472) Ebola virus Chemical and physical data Remdesivir was rapidly pushed through clinical trials due to the Formula C27H35N6O8P West African Ebola virus epidemic of 2013–2016, eventually Molar mass 602.585 g·mol−1 being used in at least one human patient despite its early 3D model Interactive image (http development stage at the time. Preliminary results were (JSmol) promising and it was used in the emergency setting during the s://chemapps.stolaf.ed Kivu Ebola epidemic that started in 2018 along with further u/jmol/jmol.php?model clinical trials, until August 2019, when Congolese health officials =Nc1ncnn2c1ccc2C announced that it was significantly less effective than monoclonal 3%28C%23N%29C%2 antibody treatments such as mAb114 and REGN-EB3. The trials, 8O%29C%28O%29 however, established its safety profile.[8][9][10][11][12][13][14][15] C%28O3%29COP%2 8%3DO%29%28Oc4cc ccc4%29NC%28C%29 Novel coronavirus (2019-nCoV) C%28%3DO%29OC In response to the 2019–20 Wuhan coronavirus outbreak induced C%28CC%29CC) by coronavirus 2019-nCoV, Gilead provided remdesivir for a SMILES "small number of patients" in collaboration with Chinese medical Nc1ncnn2c1ccc2C3(C#N)C(O)C(O)C(O3)CO authorities for studying its effects.[16] Gilead also started P(=O)(Oc4ccccc4)NC(C)C(=O)OCC(CC)C C laboratory testing of remdesivir against 2019-nCoV. Gilead stated that remdesivir was "shown to be active" against SARS and InChI [17] InChI=1S/C27H35N6O8P/c1-4-18(5-2)13-38-2 MERS in animals. 6(36)17(3)32-42(37,41-19-9-7-6-8-10-19)3 9-14-21-23(34)24(35)27(15-28,40-21)22-1 In late January 2020, remdesivir was administered to the first US 2-11-20-25(29)30-16-31-33(20)22/h6-12,1 6-18,21,23-24,34-35H,4-5,13-14H2,1-3H3, patient to be confirmed to be infected by 2019-nCoV, in (H,32,37)(H2,29,30,31)/t17-,21+,23+,24+,2 Snohomish County, Washington, for "compassionate use" after he 7-,42-/m0/s1 Key:RWWYLEGWBNMMLJ-YSOARWBDSA- progressed to pneumonia. While no broad conclusions were made N 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 The active form of remdesivir, GS-441524, shows promise for treating Feline coronavirus.[23] 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 confuses viral RNA polymerase and evades proofreading by viral exonuclease (ExoN)goog, 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 Galidesivir MK-608 NITD008 References 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" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551389). Nature. 531 (7594): 381–5. Bibcode:2016Natur.531..381W (https://ui.adsabs.harvard.edu/abs/2016Natur.531..3 81W). doi:10.1038/nature17180 (https://doi.org/10.1038%2Fnature17180). PMC 5551389 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551389). PMID 26934220 (https://pubmed. ncbi.nlm.nih.gov/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" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338263). Scientific Reports. 7 (1): 43395. Bibcode:2017NatSR...743395L (https://ui.adsabs.harvard.edu/abs/20 17NatSR...743395L). doi:10.1038/srep43395 (https://doi.org/10.1038%2Fsrep43395). PMC 5338263 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338263). PMID 28262699 (https://pubmed.ncbi.nlm.nih.gov/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" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567817). Science Translational Medicine. 9 (396): eaal3653. doi:10.1126/scitranslmed.aal3653 (https://doi.or g/10.1126%2Fscitranslmed.aal3653). PMC 5567817 (https://www.ncbi.nlm.nih.gov/pmc/arti cles/PMC5567817). PMID 28659436 (https://pubmed.ncbi.nlm.nih.gov/28659436). 4. "Remdesivir Under Study as Treatment for Novel Coronavirus" (https://www.medscape.com/ viewarticle/924964). Medscape. Retrieved 11 February 2020. 5. "Experimental Ebola drug 'remdesivir' may help protect against Nipah virus, say scientists" (https://www.timesnownews.com/health/article/experimental-ebola-drug-remdesivir-may-hel p-protect-against-nipah-virus-say-scientists/430329). Times Now Digital. 3 June 2019. 6. "Scientists Claim Drug Designed to Beat Ebola Also Fights Off Nipah" (https://thewire.in/hea lth/nipah-virus-ebola-cure-remdesivir). 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" (https://www.washingtonpost.com/world/asia_pacific/c oronavirus-china-live-updates/2020/02/10/67115416-4b9a-11ea-bf44-f5043eb3918a_story. html). 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" (https:// web.archive.org/web/20170728083042/https://medlineplus.gov/news/fullstory_166953.html) . Archived from the original (https://medlineplus.gov/news/fullstory_166953.html) 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" (http://www.jpeocbd.osd.mil/Packs/Doc Handler.ashx%3FDocID%3D700&ved=0ahUKEwjE-MD29LTQAhUMlJQKHZc1Ar4QFgh9M BI&usg=AFQjCNGCWr-rWuTyEhr1EfI3pL_T838oqA&sig2=rzvoYXRwM23Oc5aXyAKuwg). 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 (https://doi.or g/10.1093%2Fofid%2Fofv130.02). 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" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551389). Nature. 531 (7594): 381–5. Bibcode:2016Natur.531..381W (https://ui.adsabs.harvard.edu/abs/2016Natur.531..3 81W). doi:10.1038/nature17180 (https://doi.org/10.1038%2Fnature17180). PMC 5551389 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551389). PMID 26934220 (https://pubmed. ncbi.nlm.nih.gov/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" (https://www.ncbi.nlm.nih.gov/pm c/articles/PMC4967715). Lancet. 388 (10043): 498–503. doi:10.1016/S0140- 6736(16)30386-5 (https://doi.org/10.1016%2FS0140-6736%2816%2930386-5). 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