GS-443902 trisodium

GS-443902 trisodium (GS-441524 triphosphate trisodium) is a potent viral RNA-dependent RNA-polymerases (RdRp) inhibitor with IC50s of 1.1 µM, 5 µM for RSV RdRp and HCV RdRp, respectively. GS-443902 trisodium is the active triphosphate metabolite of Remdesivir (GS-5734)[1][2].

Signaling Pathways >> Anti-infection >> HCV

Research Areas >> Infection

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA/RNA Synthesis

Signaling Pathways >> Anti-infection >> SARS-CoV

Signaling Pathways >> Anti-infection >> RSV

IC50: 1.1 µM (RSV RdRp) and 5 µM (HCV RdRp)[1][2]

In a continuous 72 h incubation of 1 µM Remdesivir (GS-5734), the GS-443902 trisodium (GS-441524 triphosphate trisodium; Remdesivir metabolite trisodium) level is measured at 2, 24, 48 and 72 h, and reaches a Cmax of 300, 110, and 90 pmol/million cells in macrophages, HMVEC, and HeLa cells lines respectively[1]. GS-443902 trisodium (compound 8a) is a triphosphates (TP) derivative[2]. GS-443902 trisodium (NTP; 0.01, 0.1, 1, 10, 100 μM) inhibits RSV RdRp-catalysed RNA synthesis by incorporating into the nascent viral RNA transcript and causing its premature termination. GS-5734 selectively inhibits EBOV replication by targeting its RdRp and inhibiting viral RNA synthesis following efficient intracellular conversion to GS-443902 sodium[3].

Remdesivir (GS-5734; 10 mg kg; i.v.) rapidly distributes into peripheral blood mononuclear cells (PBMCs), and efficient conversion to GS-443902 trisodium (Remdesivir metabolite trisodium; NTP) is apparent within 2 h of dose administration in rhesus monkeys. In PBMCs, GS-443902 trisodium represents the predominant metabolite and is persistent with a t1/2 of 14 h and levels required for >50% virus inhibition for 24 hours[3].

[1]. Siegel D, et al. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. Med Chem. 2017 Mar 9;60(5):1648-1661.

[2]. Warren TK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016 Mar 17;531(7594):381-5.

[3]. Cho A, et al. Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2705-7.