B8398-5 | Remdesivir (GS-5734) [1809249-37-3] Clinisciences

Background

Remdesivir (GS-5734) is an antiviral nucleoside analogue that inhibits murine hepatitis virus (MHV) with similar EC50 as SARS-CoV and MERS-CoV.

Coronaviruses (CoVs) are positive-sense, single-stranded RNA viruses that infect a wide range of animal hosts. In humans, CoVs were recognized as typically causing colds and pneumonia until the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 from zoonotic sources.

GS-5734 is the monophosphoramidate prodrug of the C-adenosine nucleoside analogue GS-441524. In delayed brain tumor (DBT) cells infected with MHV, GS-5734 inhibited MHV more potently than GS-441524, with a GS-5734 EC50 of 0.03 μM. Furthermore, EC50 values were determined after treatment with GS-441524 and GS-5734 in SARS-CoV- and MERS-CoV-infected primary human airway epithelial cell (HAE) cultures. Mean EC50 values for both viruses were approximately 0.86 μM for GS-441524 and 0.074 μM for GS-5734.

In vivo, GS-5734-resistant SARS-CoV is attenuated in its ability to cause disease and replicates less efficiently than WT virus in robust mouse models of human SARS-CoV disease. Moreover, Remdesivir (GS-5734) is in clinical trail for the treatment of people with Ebola Virus disease.

Reference:

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). PMID: 29511076.

Chemical Properties

Storage	Store at -20°C
M.Wt	602.58
Cas No.	1809249-37-3
Formula	C₂₇H₃₅N₆O₈P
Solubility	insoluble in H2O; insoluble in EtOH; ≥51.4 mg/mL in DMSO
Chemical Name	2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
SDF	Download SDF
Canonical SMILES	NC1=NC=NN2C1=CC=C2[C@@]3(C#N)[C@H](O)[C@H](O)[C@@H](COP(OC4=CC=CC=C4)(N[C@@H](C)C(OCC(CC)CC)=O)=O)O3
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment:[1]
Cell lines	Murine astrocytoma delayed brain tumor (DBT) cells
Reaction Conditions	24 h incubation
Applications	In DBT cells infected with murine hepatitis virus (MHV), treatment with increasing concentrations of GS-5734 resulted in up to a 6-log₁₀ decrease in viral titer, and virus was undetectable by plaque assay at concentrations above 0.5 μM GS-5734. GS-5734 inhibited MHV more potently than GS-441524, with an EC50 value of 0.03 μM. In addition, GS-5734 only exhibited minimal cytotoxicity within the tested range.
Animal experiment:[2]
Animal models	A rhesus monkey model of Ebola virus (EBOV) disease (EVD)
Dosage form	10 mg/kg Once daily by intravenous route for 12 days
Applications	GS-5734 resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals.
Note	The technical data provided above is for reference only.
	References: 1. Agostini ML, Andres EL, Sims AC, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) Is mediated by the viral polymerase and the proofreading exoribonuclease. mBio, 2018, 9(2): e00221-18. 2. Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature, 2016, 531(7594): 381-385.

Quality Control

Purity = 99.32%

Chemical structure

Remdesivir (GS-5734) [1809249-37-3]

Referentie B8398-5

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