RNA-dependent RNA polymerase (RdRp) is an essential enzyme for virus replication and transcription, controlling the two important processes of viral RNA. RdRps catalyzes the formation of phosphodiester bonding between ribonucleotides, which depends on the RNA template. This process initiates from the 3′-end of the template in a primer-dependent or independent manner, moving in the 5′-3′ direction. Additionally, the core structural features of RdRps are conserved in various viruses. Therefore, RdRp has become a common target for the treatment of viral infections.

AVG-233 is a potent and orally bioavailable RdRp inhibitor.

From: Kumar R, Maurya SK, et al. RSC Med Chem. 2020 Dec 23;12(3):306-320.

AVG-233 prevents the initiation of the viral polymerase complex at the promoter. This agent has nanomolar activity against the respiratory syncytial virus (RSV) and its RdRp with EC50s of 60 nM and 80 nM, respectively.

According to the experiments in vitro, AVG-233 (1-100 μM) blocks 3′-RNA extension elongation but does not interfere with 3′-RNA extension by up to three nucleotides after de novo initiation from the promoter or back-priming. AVG-233 binding site is present in the L1-1749 fragment. AVG-233 suppresses RNA synthesis by the L1-1749 fragment in a dose-dependent manner with an IC50 value of 13.7 μM. Furthermore, it does not exhibit measurable cytotoxicity within the testable concentration range after 48 h of cell exposure.

Besides, the RdRp inhibitor exhibits effective effects in vivo. AVG-233 (50-100 mg/kg; i.g.; once) decreases lung viral load of 0.89 log10 TCID50/mL in the RSV mouse model. Moreover, AVG-233 exhibits an oral bioavailability of ~34% and an acceptable half-life in mouse circulation exceeding 5 h after oral gavage. Maximal plasma concentrations after a single dose at 20 mg/kg orally were ~2 μM.

In conclusion, AVG-233 is a potent and orally active RdRp inhibitor, that can be used to research RSV infections.

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