AVG-233 is a potent, orally active RNA dependent RNA polymerase (RdRp) inhibitor. AVG-233 prevents initiation of the viral polymerase complex at the promoter. AVG-233 binding site is present in the L1-1749 fragment. AVG-233 has nanomolar activity against both RSV strains and clinical RSV isolates (EC50=0.14-0.31 μM). AVG-233 can be used for research of respiratory syncytial virus (RSV)[1][2].
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[1].
AVG-233 (20 μM) reduces virus yield of RSV A2-L19F (EC50=0.31 μM), RSV strain 2-20 (EC50=0.14 μM) and RSV clinical isolate 718 (EC50=0.2 μM) [1].
AVG-233 (1.25-40 μM; 0-300 s) suppresses RNA synthesis by the L1-1749 fragment in a dose-dependent manner with an IC50 value of 13.7 μM. AVG-233 bounds L and the L1-1749 fragment with similar affinities (dissociation constants (KD's) are 38.3 μM and 53.1 μM, respectively)[2].
AVG-233 (50-100 mg/kg; i.g.; once) decreases lung viral load in the RSV mouse model[2].
AVG-233 (2-20 mg/kg; i.v. and p.o.; once; male CD-1 mice) has good orally bioavailable and the maximum plasma concentration about 2 μM[1].
| Animal Model: | Female Balb/cJ mice with recRSV-mKate xenograft[2] |
| Dosage: | 50 and 100 mg/kg |
| Administration: | Oral gavage; once |
| Result: | Reduced in lung viral load of 0.89 log10 TCID50 (median tissue culture infectious dose)/mL. |
| Animal Model: | Male CD-1 mice (27-29 g)[1] | ||||||||||||||||||||||||
| Dosage: | 2 mg/kg (i.v.) and 20 mg/kg (p.o.) | ||||||||||||||||||||||||
| Administration: | Intravenous injection and oral administration; once, obtains blood samples at pre-dose and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h post-dosing | ||||||||||||||||||||||||
| Result: |
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[1]. Cox RM, et, al. Development of an allosteric inhibitor class blocking RNA elongation by the respiratory syncytial virus polymerase complex. J Biol Chem. 2018 Oct 26;293(43):16761-16777.
[2]. Sourimant J, et, al. Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase. Sci Adv. 2022 Jun 24;8(25):eabo2236.