biostudies-literatureJi XShandong Provincial Key Research and Development ProjectThe Agency for Medical Research and DevelopmentThe Japan Society for the Promotion of Science KAKENHIScience Foundation for Outstanding Young Scholars of Shandong ProvinceForeign Cultural and Educational Experts Project5987https://www.ebi.ac.uk/biostudies/studies/S-EPMC9505734biostudies-literatureUnknown27(18)Hepatitis B virus (HBV) capsid protein (Cp) is necessary for viral replication and the maintenance of viral persistence, having become an attractive target of anti-HBV drugs. To improve the water solubility of HBV capsid protein allosteric modulator (CpAM) NVR 3-778, a series of novel carboxylic acid and phosphate prodrugs were designed and synthesized using a prodrug strategy. In vitro HBV replication assay showed that these prodrugs maintained favorable antiviral potency (EC<sub>50</sub> = 0.28-0.42 µM), which was comparable to that of NVR 3-778 (EC<sub>50</sub> = 0.38 µM). More importantly, the cytotoxicity of prodrug <b>N8</b> (CC<sub>50</sub> > 256 µM) was significantly reduced compared to NVR 3-778 (CC<sub>50</sub> = 13.65 ± 0.21 µM). In addition, the water solubility of prodrug <Molecules (Basel, Switzerland)Design, Synthesis, and Evaluation of a Set of Carboxylic Acid and Phosphate Prodrugs Derived from HBV Capsid Protein Allosteric Modulator NVR 3-778.PMC9505734No. 2019JZZY021011ZR2020JQ31GXL20200015001Grant No. JP20H03499, JP61H02449Grant Nos. JP21jm0210068, JP22fk0310504, JP22wm0325007, JP22fk0310511Ren YLiu XZhan PJi XZhao SKobayashi CKang DJiang XJia RZhang XGao ZWatashi KHu LfalseDesign, Synthesis, and Evaluation of a Set of Carboxylic Acid and Phosphate Prodrugs Derived from HBV Capsid Protein Allosteric Modulator NVR 3-778.Hepatitis B virus (HBV) capsid protein (Cp) is necessary for viral replication and the maintenance of viral persistence, having become an attractive target of anti-HBV drugs. To improve the water solubility of HBV capsid protein allosteric modulator (CpAM) NVR 3-778, a series of novel carboxylic acid and phosphate prodrugs were designed and synthesized using a prodrug strategy. In vitro HBV replication assay showed that these prodrugs maintained favorable antiviral potency (EC<sub>50</sub> = 0.28-0.42 µM), which was comparable to that of NVR 3-778 (EC<sub>50</sub> = 0.38 µM). More importantly, the cytotoxicity of prodrug <b>N8</b> (CC<sub>50</sub> > 256 µM) was significantly reduced compared to NVR 3-778 (CC<sub>50</sub> = 13.65 ± 0.21 µM). In addition, the water solubility of prodrug <2022-01-01T00:00:00Z2022 Sep2025-06-01T00:11:20.515Z2025-02-19T00:41:50.819ZS-EPMC95057343614471510.3390/molecules27185987