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=== Mechanism of action ===
=== Mechanism of action ===
As an [[adenosine]] nucleotide triphosphate analog, the [[active metabolite]] of remdesivir interferes with the action of viral [[RNA-dependent RNA polymerase]] and evades [[proofreading (biology)|proofreading]] by viral [[exoribonuclease]] (ExoN), causing a decrease in viral RNA production.<ref name="Scavone_2020"/><ref name="Ferner2020">{{cite journal | vauthors = Ferner RE, Aronson JK | title = Remdesivir in covid-19 | journal = BMJ | volume = 369 | pages = m1610 | date = April 2020 | pmid = 32321732 | doi = 10.1136/bmj.m1610 |doi-access=free| url = https://www.bmj.com/content/369/bmj.m1610.long }}</ref> In some viruses such as the [[respiratory syncytial virus]] it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain.<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> Hence remdesivir is classified as a delayed chain terminator.<ref name = "Eastman_2020" />
As an [[adenosine]] nucleotide triphosphate analog, the [[active metabolite]] of remdesivir interferes with the action of viral [[RNA-dependent RNA polymerase]] and evades [[proofreading (biology)|proofreading]] by viral [[exoribonuclease]] (ExoN), causing a decrease in viral RNA production.<ref name="Scavone_2020"/><ref name="Ferner2020">{{cite journal | vauthors = Ferner RE, Aronson JK | title = Remdesivir in covid-19 | journal = BMJ | volume = 369 | pages = m1610 | date = April 2020 | pmid = 32321732 | doi = 10.1136/bmj.m1610 |doi-access=free| url = https://www.bmj.com/content/369/bmj.m1610.long }}</ref> In some viruses such as the [[respiratory syncytial virus]] it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain.<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> For the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2 arrest of RNA synthesis occurs after incorporation of three additional nucleotides.<ref>{{cite journal |last1=Gordon |first1=Calvin |last2=Tchesnokov |first2=Egor |last3=Feng |first3=Joy |last4=Porter |first4=Danielle |last5=Gotte |first5=Matthias |title=The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus |journal=J Biol Chem |date=2020 Apr 10 |volume=295 |issue=15 |page=4773 |pages=4779 |doi=10.1074/jbc.AC120.013056. |pmid=32094225 |accessdate=Epub 2020 Feb 24}}</ref> <ref>{{cite journal |last1=Gordon |first1=Calvin |last2=Tchesnokov |first2=Egor |last3=Woolner |first3=Emma |last4=Perry |first4=Jason |last5=Feng |first5=Joy |last6=Porter |first6=Danielle |last7=Gotte |first7=Matthias |title=Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency |journal=J Biol Chem |date=2020 Apr 13 |doi=10.1074/jbc.RA120.013679. |pmid=32284326 |accessdate=2020 Apr 13}}</ref> Hence remdesivir is classified as a delayed chain terminator.<ref name = "Eastman_2020" />


=== Pharmacokinetics ===
=== Pharmacokinetics ===

Revision as of 18:43, 10 May 2020

Remdesivir
Clinical data
Pronunciation/rɛmˈdɛsɪvɪər/ rem-DESS-i-veer
Other namesGS-5734
AHFS/Drugs.comProfessional Drug Facts
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
ChEMBL
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 is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences.[2] As of 2020, remdesivir is being tested as a specific treatment for COVID-19, and has been authorized for emergency use in the U.S. and approved for use in Japan for people with severe symptoms.[3][4][5] It may shorten the time it takes to recover from the infection.[6][7] Treatment is given by injection into a vein.[8][9]

Side effects may include liver inflammation and an infusion related reaction with nausea, low blood pressure, and sweating.[10] It is a pro-drug that is converted in the body into GS-441524, a ribonucleotide analog.

Earlier studies found antiviral activity against several RNA viruses including SARS coronavirus and MERS coronavirus, but it is not approved for any indication.[2][3] Remdesivir was originally developed to treat Ebola virus disease and Marburg virus disease but was ineffective for these viral infections.[2]

Side effects

The most common adverse effects in studies of remdesivir for COVID‑19 include respiratory failure and organ impairment, including low albumin, low potassium, low count of red blood cells, low count of platelets that help with clotting, and yellow discoloration of the skin.[11] Other reported side effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), and infusion site reactions.[9]

Other possible side effects of remdesivir include:

  • Infusion‐related reactions. Infusion‐related reactions have been seen during a remdesivir infusion or around the time remdesivir was given.[12] Signs and symptoms of infusion‐related reactions may include: low blood pressure, nausea, vomiting, sweating, and shivering.[12]
  • Increases in levels of liver enzymes, seen in abnormal liver blood tests.[12] Increases in levels of liver enzymes have been seen in people who have received remdesivir, which may be a sign of inflammation or damage to cells in the liver.[12]

Research

Remdesivir was created and developed by Gilead Sciences, under the direction of scientist Tomáš Cihlář,[13] as part of Gilead's research and development program on treatments for Ebola virus disease and Marburg virus infections.[14] Gilead Sciences subsequently discovered that remdesivir had antiviral activity in vitro against multiple filoviruses, pneumoviruses, paramyxoviruses, and coronaviruses.[15]

Ebola

In October 2015, the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) announced preclinical results that remdesivir had blocked the Ebola virus in Rhesus monkeys. Travis Warren, who has been a USAMRIID principal investigator since 2007, said that the "work is a result of the continuing collaboration between USAMRIID and Gilead Sciences".[16] 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).[16] As a result of this work, it was recommended that remdesivir "should be further developed as a potential treatment."[14][16]

Remdesivir was rapidly pushed through clinical trials due to the West African Ebola virus epidemic of 2013–2016, eventually being used in people with the disease. Preliminary results were promising; 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.[14][17][18][19][20][21][22][23]

COVID-19

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

As of April 2020, remdesivir was viewed as the most promising treatment for COVID-19,[24] and was included among four treatments under evaluation in the international Solidarity trial[25][26][27] and European Discovery trial.[28] The FDA stated on 1 May 2020, that it is "reasonable to believe" that known and potential benefits of remdesivir outweigh its known and potential risks, in some specific populations hospitalized with severe COVID‑19.[3]

On 29 April 2020, the National Institute of Allergy and Infectious Diseases (NIAID) announced that remdesivir was better than a placebo in reducing time to recovery for people hospitalized with advanced COVID‑19 and lung involvement.[7] Previously data from one randomized controlled trial was released early in error and before peer review; it did not show improvement. Gilead Sciences stated that due to low enrollment the study was halted while a non-associated researcher stated it does mean if there is any benefit, then that benefit will be small.[29]

In January 2020, Gilead began laboratory testing of remdesivir against SARS-CoV-2, stating that remdesivir had been shown to be active against severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in animal models.[30][31][32] On 21 January 2020, the Wuhan Institute of Virology applied for a Chinese "use patent", for treating COVID‑19.[33]

In a trial in China over February-March 2020, remdesivir was not effective in reducing the time for improvement from COVID‑19 or deaths, and caused various adverse effects, requiring the investigators to terminate the trial.[11]

In March 2020, a small trial of remdesivir in rhesus macaque monkeys with COVID‑19 infections found that it prevents disease progression.[34][35] On 18 March 2020, the World Health Organization (WHO) announced the launch of a trial that would include one group treated with remdesivir.[26][36] Other clinical trials are underway or planned.[37][38][39][40][41][42][43][44][45][46]

Early data from a controlled trial carried out by the U.S. National Institutes of Health, suggests that remdesivir is effective in reducing the recovery time from 15 to 11 days in people seriously ill with COVID‑19.[7] This data contradicted findings from a trial carried out in China, that showed remdesivir was not effective in treating COVID‑19.[11]

In April 2020, the European Medicines Agency (EMA) started a 'rolling review' of data on the use of remdesivir in COVID‑19.[47]

Access

On 17 March 2020, the drug was provisionally approved for use for COVID‑19 patients in a serious condition as a result of the outbreak in the Czech Republic.[48] On 20 March 2020, United States President Donald Trump announced that remdesivir was available for "compassionate use" for people with COVID‑19; FDA Commissioner Stephen Hahn confirmed the statement at the same press conference.[49] On 23 March 2020, Gilead voluntarily suspended access 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.[24][50] In April 2020, the European Medicines Agency (EMA) provided recommendations on compassionate use of remdesivir for COVID‑19 in the EU.[51]

As of 11 April 2020, access in Canada was only to those who will be involved in a clinical trial.[52]

On 1 May 2020, the U.S. Food and Drug Administration granted Gilead Emergency Use Authorization of remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID‐19.[4][12] Severe COVID‐19 is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO), a heart‐lung bypass machine.[53][12][54][55] Distribution of remdesivir under the EUA will be controlled by the U.S. government for use consistent with the terms and conditions of the EUA.[12] Gilead will supply remdesivir to authorized distributors, or directly to a U.S. government agency, who will distribute to hospitals and other healthcare facilities as directed by the U.S. Government, in collaboration with state and local government authorities, as needed.[12]

On 7 May 2020, Japan's Ministry of Health, Labour and Welfare approved the drug for use in Japan, in a fast-tracked process based on the U.S. emergency authorization.[5]

Gilead stated they were donating 1.5 million vials for emergency use[54] and estimated, as of April 2020, they had enough drug for 140,000 treatment courses and expect to have 500,000 courses by October 2020, and one million courses by the end of 2020.[56][57]

The initial distribution of the drug in the U.S. was tripped up by seemingly capricious decision-making and finger-pointing.[58]

Pharmacology

Activation

Activation of remdesivir into its active triphosphate metabolite[59]

Remdesivir is a ProTide (Prodrug of nucleoTide) that is able to diffuse into cells where it is converted to GS-441524 mono-phosphate via the actions of esterases and a phosphoramidase; this in turn is further phosphorylated to its active metabolite triphosphate by nucleoside-phosphate kinases.[60]

Mechanism of action

As an adenosine nucleotide triphosphate analog, the active metabolite of remdesivir interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production.[2][61] In some viruses such as the respiratory syncytial virus it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain.[62] For the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2 arrest of RNA synthesis occurs after incorporation of three additional nucleotides.[63] [64] Hence remdesivir is classified as a delayed chain terminator.[59]

Pharmacokinetics

In non-human primates, the plasma half-life of the prodrug is 20 minutes, but the activated triphosphate form has sustained intracellular levels.[59]

Resistance

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.[65]

Interactions

Remdesivir is at least partially metabolized by the cytochrome P450 enzymes CYP2C8, CYP2D6, and CYP3A4.[66] Blood plasma concentrations of remdesivir are expected to decrease if it is administered together with cytochrome P450 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin, primidone, and St John's wort.[67]

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.[68][69] 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 one additional 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.

Terminology

Remdesivir is the international nonproprietary name (INN)[70] while the development code name was GS-5734.[71]

Other animals

Remdesivir was shown in 2019 to have possible promise for treating feline infectious peritonitis caused by a coronavirus.[72] It has not been evaluated or approved by the Food and Drug Administration (FDA) for the treatment of feline coronavirus or feline infectious peritonitis but has been available since 2019 through websites and social media as an unregulated black market substance as confirmed by the UC Davis School of Veterinary Medicine.[73]

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Further reading

External links

Wikimedia Commons has media related to Remdesivir.
Scholia has a profile for remdesivir (Q28209496).
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