An RSV fusion inhibitor
JNJ-53718678 is an inhibitor of respiratory syncytial virus (RSV) fusion.1 JNJ-53718678 binds to and stabilizes the RSV fusion protein in its prefusion conformation.2 It reduces RSV replication in RSV-infected HeLa cells (IC50 = 0.5 nM) with a 50% cytotoxic concentration (CC50) of greater than 50 ?M.1 JNJ-53718678 (4-100 mg/kg), administered prior to infection, reduces RSV viral titers in lavaged-lung tissue and viral RNA production in the lungs in a semi-permissive cotton rat model of RSV.2 JNJ-53718678 also reduces RSV viral titers in bronchoalveolar lavage fluid (BALF) in a fully replicative neonatal lamb model of RSV when administered at doses of 5 and 25 mg/kg per day.
1.Vendeville, S., Tahri, A., Hu, L., et al.Discovery of 3-({5-Chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (JNJ-53718678), a potent and orally bioavailable fusion inhibitor of respiratory syncytial virusJ. Med. Chem.63(15)8046-8058(2020) 2.Roymans, D., Alnajjar, S.S., Battles, M.B., et al.Therapeutic efficacy of a respiratory syncytial virus fusion inhibitorNat. Commun.8(1)167(2017)
Cell experiment: | The antiviral activity of JNJ-678 (JNJ-53718678) against hMPV is evaluated using a cellular infectious assay in 96-well plates in which Vero/TMPRSS2 cells are infected with recombinant hMPV65. Cells are treated with different concentrations of JNJ-678 (JNJ-53718678) and then infected with recombinant hMPV (1×104 PFU per well). Three days post-virus exposure, viral replication is quantified by measuring fluorescence and the EC50 is calculated[1]. |
Animal experiment: | Rats[1]Cotton rats receive either a single dose at 24?h after viral infection or once-daily doses of 40?mg/kg JNJ-678 (JNJ-53718678) by oral gavage, at 24, 48, and 72?h after viral infection. The decrease of viral replication in all experiments is compared to challenged animals that received only the vehicle[1]. |
参考文献: [1]. Roymans D, et al. Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor. Nat Commun. 2017 Aug 1;8(1):167. | |
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