remdesivir remdesivir remdesivir, sold under the brand name veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company gilead sciences. it is administered via injection into a vein. during the covid‑19 pandemic, remdesivir was approved or authorized for emergency use to treat covid‑19 in numerous countries. remdesivirclinical datapronunciation/rɛmˈdɛsɪvɪər/ rem-dess-i-veer trade namesvekluryother namesgs-5734, rdvahfs/drugs.commonographmedlineplusa620033license data eu ema: by inn us dailymed: remdesivir pregnancycategory au: b2 routes ofadministrationintravenousatc codej05ab16 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only and emergency use authorization eu: rx-only identifiers iupac name (2s)-2-propionic acid 2-ethyl-butyl ester cas number1809249-37-3pubchem cid121304016drugbankdb14761chemspider58827832unii3qki37eehekeggd11472chebichebi:145994chemblchembl4065616echa infocard100.302.974 chemical and physical dataformulac27h35n6o8pmolar mass602.585 g·mol−13d model (jsmol)interactive image smiles ccc(coc(=o)(np(=o)(oc1ccccc1)oc1o((1o)o)(c#n)c1ccc2n1ncnc2n)c)cc inchi 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/s1key:rwwylegwbnmmlj-ysoarwbdsa-n remdesivir was originally developed to treat hepatitis c, and was subsequently investigated for ebola virus disease and marburg virus infections before being studied as a post-infection treatment for covid‑19. remdesivir is a prodrug that is intended to allow intracellular delivery of gs-441524 monophosphate and subsequent biotransformation into gs-441524 triphosphate, a ribonucleotide analogue inhibitor of viral rna polymerase. the most common side effect in healthy volunteers is raised blood levels of liver enzymes. the most common side effect in people with covid‑19 is nausea. side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating. the u.s. food and drug administration (fda) considers it to be a first-in-class medication. medical uses in the european union, remdesivir is indicated for the treatment of coronavirus disease 2019 (covid‑19) in adults and adolescents (aged twelve years and older with body weight at least 40 kilograms (88 lb)) with pneumonia requiring supplemental oxygen and for adults who do not require supplemental oxygen and who are at increased risk of progressing to severe covid-19. in the united states, remdesivir is indicated for use in adults and adolescents (aged twelve years and older with body weight at least 40 kilograms (88 lb)) for the treatment of covid‑19 requiring hospitalization. in january 2022, the fda expanded the indication for remdesivir to include its use in non-hospitalized adults and adolescents with positive results of direct sars-cov-2 viral testing, and who are not hospitalized and have mild-to-moderate covid‑19, and are at high risk for progression to severe covid‑19, including hospitalization or death. in april 2022, the approval was expanded to include children 28 days of age and older weighing at least 3 kilograms (6.6 lb) with positive results of direct sars-cov-2 viral testing. in november 2020, the fda issued an emergency use authorization (eua) for the combination of baricitinib with remdesivir, for the treatment of suspected or laboratory confirmed covid‑19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ecmo). in australia, it is approved for those aged four weeks of age and older with a body weight at least 3 kilograms (6.6 lb) with pneumonia requiring supplemental oxygen or those aged four weeks of age and older with body weight at least 40 kilograms (88 lb) who do not require supplemental oxygen and who are at high risk of progressing to severe covid-19. side effects the most common adverse effects in people treated with remdesivir were respiratory failure and blood biomarkers of organ impairment, including low albumin, low potassium, low count of red blood cells, low count of thrombocytes, and elevated bilirubin (jaundice). other reported adverse effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), infusion site reactions, and electrocardiogram abnormalities. remdesivir may cause infusion-related reactions, including low blood pressure, nausea, vomiting, sweating or shivering. 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. signs and symptoms of infusion-related reactions may include: low blood pressure, nausea, vomiting, sweating, and shivering. increases in levels of liver enzymes, seen in abnormal liver blood tests. 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. pharmacology activation activation of remdesivir into its active triphosphate metabolite remdesivir is a protide (prodrug of nucleotide) able to diffuse into cells, where it is converted to gs-441524 monophosphate via the actions of esterases (ces1 and ctsa) and a phosphoamidase (hint1); this in turn is further phosphorylated to its active metabolite triphosphate by nucleoside-phosphate kinases. this pathway of bioactivation is meant to occur intracellularly, but a substantial amount of remdesivir is prematurely hydrolyzed in plasma, with gs-441524 being the major metabolite in plasma, and the only metabolite remaining two hours after dosing. mechanism of action as an adenosine nucleoside triphosphate analog (gs-443902), 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. 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. 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. hence, remdesivir is classified as a direct-acting antiviral agent that works as a delayed chain terminator. pharmacokinetics in non-human primates, the plasma half-life of the prodrug is 20 minutes, with the main metabolite being the nucleoside, gs-441524. two hours post injection, the main metabolite gs-441524 is present at micromolar concentrations, whilst intact remdesivir is no longer detectable. because of this rapid extracellular conversion to the nucleoside gs-441524, some researchers have questioned whether the active nucleotide triphosphate is truly derived from remdesivir pro-drug removal or whether it occurs by gs-441524 phosphorylation, and whether direct administration of gs-441524 would constitute a cheaper and easier to administer covid‑19 drug compared to remdesivir. the activated nucleotide triphosphate form has sustained intracellular levels in pbmc and presumably in other cells as well. 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. interactions remdesivir is at least partially metabolized by the cytochrome p450 enzymes cyp2c8, cyp2d6, and cyp3a4. 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. using chloroquine or hydroxychloroquine with remdesivir may reduce the antiviral activity of remdesivir. coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir. 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. 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 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. in vitro experiments an in vitro study of remdesivir assessing antiviral activity against sars-cov-2 was performed. cells were pre-treated with the different doses of remdesivir for 1 hour, and the virus (moi of 0.05) was subsequently added to allow infection for 2 hours. the results found that remdesivir functioned well as an inhibitor of the infection. the study was published as a letter to the editor, and as such did not undergo peer review. manufacturing remdesivir requires "70 raw materials, reagents, and catalysts" to make, and approximately "25 chemical steps." some of the ingredients are extremely dangerous to humans, especially trimethylsilyl cyanide. the original end-to-end manufacturing process required 9 to 12 months to go from raw materials at contract manufacturers to finished product, but after restarting production in january 2020, gilead sciences was able to find ways to reduce the production time to six months. in january 2020, gilead began working on restarting remdesivir production in glass-lined steel chemical reactors at its manufacturing plant in edmonton, alberta. on 2 february 2020, the company flew its entire stock of remdesivir, 100 kilograms in powder form (left over from ebola research), to its filling plant in la verne, california to start filling vials. the edmonton plant finished its first new batch of remdesivir in april 2020. around the same time, fresh raw materials began to arrive from contract manufacturers reactivated by gilead in january. another challenge is getting remdesivir into patients despite the drug's "poor predicted solubility and poor stability." in june 2020, ligand pharmaceuticals revealed that gilead has been managing those issues by mixing ligand's proprietary excipient captisol (based on university of kansas research into cyclodextrin) with remdesivir at a 30:1 ratio. since that implies an enormous amount of captisol is needed to stabilize and deliver remdesivir (on top of amounts needed for several other drugs for which the excipient is already in regular use), ligand announced that it is trying to boost captisol annual manufacturing capacity to as much as 500 metric tons. on 12 may 2020, gilead announced that it had granted non-exclusive voluntary licenses to five generic drug companies in india and pakistan to manufacture remdesivir for distribution to 127 countries. the agreements were structured so that the licensees can set their own prices and will not have to pay royalties to gilead until the who declares an end to the covid‑19 emergency or another medicine or vaccine is approved for covid‑19, whichever comes first. on 23 june 2020, india granted emergency marketing approval of generic remdesivir manufactured by two gilead licensees, cipla and hetero drugs. society and culture legal status remdesivir is approved, or authorized for emergency use, to treat covid‑19 in many countries. remdesivir has been authorized for emergency use in india, singapore, and approved for use in japan, the european union, the united states, and australia for people with severe symptoms. remdesivir is the first treatment for covid‑19 to be approved by the u.s. food and drug administration (fda). the approval by the fda does not include the entire population that had been authorized to use remdesivir under an emergency use authorization (eua) originally issued on 1 may 2020. in order to ensure continued access to the pediatric population previously covered under the eua, the fda revised the eua for remdesivir to authorize the drug's use for treatment of suspected or laboratory-confirmed covid‑19 in hospitalized pediatric patients weighing 3.5 kilograms (7.7 lb) to less than 40 kilograms (88 lb) or hospitalized pediatric patients less than twelve years of age weighing at least 3.5 kilograms (7.7 lb). clinical trials assessing the safety and efficacy of remdesivir in this pediatric patient population are ongoing. australia in july 2020, remdesivir was provisionally approved for use in australia for use in adults and adolescents with severe covid‑19 symptoms who have been hospitalized. australia claims to