GS-646089 

GS-646089 is a broad-spectrum antiviral nucleoside analog that exhibits significant inhibitory activity against respiratory syncytial virus (RSV), human metapneumovirus (hMPV), rhinovirus (enterovirus) and enteroviruses. The IC₅₀ of GS-646089 targeting RNA-dependent RNA polymerase (RdRp) ranges from 43 to 46 nM. GS-646089 blocks viral replication by being converted into a triphosphate metabolite intracellularly, which competes with ATP for incorporation into nascent RNA strands and acts as an immediate chain terminator. GS-646089 is the parent compound of the double prodrug GS-7682 (HY-161877), and is used in studies of acute respiratory viral infections and infections caused by related pathogens^[1][2][3].

GS-646089 (compound 2) inhibits RSV replication in primary NHBE cells and HEp-2 cells, with EC₅₀ values of 6.23 μM and 6.83 μM, respectively; additionally, it shows no cytotoxicity against HEp-2 cells and MT4 cells at concentrations up to 50 μM^[1].
The active triphosphate metabolite (2-NTP) of GS-646089 potently inhibits the RSV RNP complex with an IC₅₀ of 0.050 μM, and exhibits high selectivity for human mitochondrial polymerase and DNA polymerase^[1].
GS-646089 potently inhibits cell-free RSV-A2 RNP complex and RdRp enzymatic activity, with IC₅₀ values of 46 nM and 43 nM, respectively^[2].
GS-646089 inhibits RSV replication in NHBE cells with an EC₅₀ of approximately 2-7 μM, and shows no cytotoxicity at concentrations up to 50 μM^[3].
GS-646089 inhibits RSV replication in HEp-2 cells with an EC₅₀ of approximately 2-7 μM; it shows no cytotoxicity to HEp-2 or MT4 cells even at the highest concentration of 50 μM^[3].
GS-646089 (10 μM; 2 h) generates low levels of intracellular active 2-NTP metabolites, indicating that the initial phosphorylation of this nucleoside is limited^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

GS-646089 (compound 2) (1.6-7.6 mg/kg; i.t.; once daily; 6 days), the active metabolite of inhaled GS-7682, achieves an average 3.6 log₁₀ reduction in RSV BAL viral load in RSV-infected African Green Monkeys, significantly inhibiting lower respiratory tract viral replication^[1].
GS-646089 (1.6-7.6 mg/kg; intratracheal nebulized aerosol; once daily; 6 days) achieves an average 3.6 log₁₀ reduction in RSV A2 viral load in African Green Monkey BAL fluid by day 5 post-infection, with sustained lower viral loads relative to vehicle controls through day 11^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

291.26

C₁₂H₁₃N₅O₄

1770840-57-7

NC1=NC=NN2C1=CC=C2[C@H]3[C@H](O)[C@H](O)[C@](CO)(C#N)O3

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. Siegel D S, et al. Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4′-CN-4-Aza-7, 9-Dideazaadenosine C-Nucleoside with Broad-Spectrum Potency Against Pneumo-and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys[J]. bioRxiv, 2024: 2024.04. 17.589937.

  [2]. Suresh RR, et al. Prodrug strategies in developing antiviral nucleoside analogs. RSC Med Chem. 2026;17(1):105-131. Published 2026 Jan 2.  [Content Brief]

  [3]. Siegel DS, et al. Discovery of GS-7682, a Novel 4'-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys. J Med Chem. 2024;67(15):12945-12968.  [Content Brief]