Remdesivir

Identification

Name
Remdesivir
Accession Number
DB14761
Type
Small Molecule
Groups
Investigational
Description

Remdesivir, or GS-5734, is an adenosine triphosphate analog first described in the literature in 2016 as a potential treatment for Ebola.1 In 2017, its activity against the coronavirus family of viruses was also demonstrated.2 Remdesivir is also being researched as a potential treatment to SARS-CoV2, the coronavirus responsible for COVID-19.4

Structure
Thumb
Synonyms
  • Remdesivir
  • Remdésivir
  • Remdesivirum
External IDs
GS 5734 / GS-5734
Categories
UNII
3QKI37EEHE
CAS number
1809249-37-3
Weight
Average: 602.585
Monoisotopic: 602.225399109
Chemical Formula
C27H35N6O8P
InChI Key
RWWYLEGWBNMMLJ-YSOARWBDSA-N
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/s1
IUPAC Name
2-ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate
SMILES
CCC(CC)COC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@](C#N)([C@H](O)[C@@H]1O)C1=CC=C2N1N=CN=C2N)OC1=CC=CC=C1

Pharmacology

Indication

Remdesivir was originally investigated as a treatment for Ebola virus, but has potential to treat a variety of RNA viruses.1 Its activity against the coronavirus (CoV) family of viruses, such as SARS-CoV and MERS-CoV, was described in 2017,2 and it is also being investigated as a potential treatment for SARS-CoV2 infections.4

Pharmacodynamics

Dosing was predicted to be twice daily to maintain therapeutic concentrations required for treatment of CoV infections.2 However, current clinical trials will use a regimen of 200mg once daily on the first day, followed by 100mg once daily for another 9 days.6,7,8

Mechanism of action

Remdesivir is a nucleoside analog that is expected to inhibit the action of RNA polymerase.3 By incorporating into RNA, additional nucleotides cannot be added, terminating RNA transcription.3 Viruses with mutations in RNA polymerase to develop partial resistance to remdesivir have been shown to be less infective.3

TargetActionsOrganism
UReplicase polyprotein 1ab
inhibitor
SARS-CoV
URNA-directed RNA polymerase L
inhibitor
Zaire ebolavirus (strain Mayinga-76)
Absorption

A 10mg/kg intravenous dose given to cynomolgus monkeys distributes to the testes, epididymis, eyes, and brain within 4h.1

Volume of distribution

Data regarding the volume of distribution of remdesivir is not readily available.

Protein binding

Data regarding the protein binding of remdesivir is not readily available.

Metabolism

Remdesivir is predominantly metabolized to a triphosphate metabolite.1,2

Route of elimination

Data regarding the route of elimination of remdesivir is not readily available.

Half life

A 10mg/kg intravenous dose in non human primates has a plasma half life of 0.39h.1 The nucleoside triphosphate metabolite has a half life of 14h in non human primates.1 The nucleoside triphosphate metabolite has a half life of approximately 20 hours in humans.2

Clearance

Data regarding the clearance of remdesivir is not readily available.

Toxicity

Data regarding overdoses of remdesivir are not readily available. Overdoses of other nucleoside analogs like acyclovir can be managed with symptomatic and supportive treatment.5

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

References

General References
  1. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen SS, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S: Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 2. [PubMed:26934220]
  2. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS: Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017 Jun 28;9(396). pii: 9/396/eaal3653. doi: 10.1126/scitranslmed.aal3653. [PubMed:28659436]
  3. 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: Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. doi: 10.1128/mBio.00221-18. [PubMed:29511076]
  4. de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, Scott D, Cihlar T, Feldmann H: Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020 Feb 13. pii: 1922083117. doi: 10.1073/pnas.1922083117. [PubMed:32054787]
  5. Vander T, Medvedovsky M, Herishanu Y: Encephalopathy induced by oral acyclovir in a patient with normal renal function. J Infect. 2003 May;46(4):286. doi: 10.1053/jinf.2002.1119. [PubMed:12799156]
  6. Ko WC, Rolain JM, Lee NY, Chen PL, Huang CT, Lee PI, Hsueh PR: Arguments in favor of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents. 2020 Mar 5:105933. doi: 10.1016/j.ijantimicag.2020.105933. [PubMed:32147516]
  7. NIH: Clinical Trial NCT04252664 [Link]
  8. NIH: Clinical Trial NCT04257656 [Link]
External Links
ChemSpider
58827832
ChEMBL
CHEMBL4065616
Wikipedia
Remdesivir

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentEbola / Persistent Ebola Virus1
2RecruitingTreatmentCorona virus infection1
2, 3RecruitingTreatmentEbola Viruses1
3Not Yet RecruitingTreatmentCorona virus infection1
3RecruitingTreatment2019-nCoV1
3RecruitingTreatment2019-nCoV / Remdesivir1
3RecruitingTreatmentCoVID-192
Not AvailableAvailableNot AvailableCoronavirus Disease 20191

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.339 mg/mLALOGPS
logP2.2ALOGPS
logP2.01ChemAxon
logS-3.2ALOGPS
pKa (Strongest Acidic)10.23ChemAxon
pKa (Strongest Basic)0.65ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area203.55 Å2ChemAxon
Rotatable Bond Count14ChemAxon
Refractivity161.81 m3·mol-1ChemAxon
Polarizability59.72 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
SARS-CoV
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Replicase polyprotein 1ab: Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.Host transl...
Gene Name
rep
Uniprot ID
P0C6X7
Uniprot Name
Replicase polyprotein 1ab
Molecular Weight
790241.63 Da
References
  1. 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: Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. doi: 10.1128/mBio.00221-18. [PubMed:29511076]
Kind
Protein
Organism
Zaire ebolavirus (strain Mayinga-76)
Pharmacological action
Unknown
Actions
Inhibitor
General Function
RNA-directed RNA polymerase that catalyzes the transcription of viral mRNAs, their capping and polyadenylation. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). The viral polymerase binds to the genomic RNA at the 3' leader promoter, and transcribes subsequently all viral mRNAs with a decreasing efficiency. The first gene is the most transcribed, and the last the least transcribed. The viral phosphoprotein acts as a processivity factor. Capping is concommitant with initiation of mRNA transcription. Indeed, a GDP polyribonucleotidyl transferase (PRNTase) adds the cap structure when the nascent RNA chain length has reached few nucleotides. Ribose 2'-O methylation of viral mRNA cap precedes and facilitates subsequent guanine-N-7 methylation, both activities being carried by the viral polymerase. Polyadenylation of mRNAs occur by a stuttering mechanism at a slipery stop site present at the end viral genes. After finishing transcription of a mRNA, the polymerase can resume transcription of the downstream gene.
Specific Function
Atp binding
Gene Name
L
Uniprot ID
Q05318
Uniprot Name
RNA-directed RNA polymerase L
Molecular Weight
252722.045 Da
References
  1. Tchesnokov EP, Feng JY, Porter DP, Gotte M: Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir. Viruses. 2019 Apr 4;11(4). pii: v11040326. doi: 10.3390/v11040326. [PubMed:30987343]

Drug created on April 23, 2019 16:25 / Updated on March 13, 2020 22:11

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