biostudies-literatureYang XNatural Science Foundation of Beijing MunicipalitySpecial Program of Peking University Health Science CenterNational Natural Science Foundation of ChinaNational Key Research and Development Program of Chinae03534https://www.ebi.ac.uk/biostudies/studies/S-EPMC12677619biostudies-literatureUnknown12(45)Current antiviral drugs targeting the hepatitis B virus (HBV) still face challenges in achieving a functional cure for chronic hepatitis B. Therefore, it is necessary to explore new therapeutic approaches and combined therapy strategies. Anticodon engineered transfer RNA (ACE-tRNA) has been widely applied in the treatment of genetic diseases caused by nonsense mutations. However, its role in antiviral therapy has not been reported yet. In this study, ACE-tRNAs are designed to target the highly conserved stop codon (UAG) of HBV core protein (HBc). All designed ACE-tRNAs can read through the stop codon of HBc. Among them, tRNA^SUAG might promote HBc phosphorylation by introducing a phosphorylatable serine into the C-terminal domain of HBc, thereby potentially reducing HBc levels anAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Anticodon Engineered Transfer RNA (tRNA<sup>SUAG</sup>) Inhibits Hepatitis B Virus Replication by Promoting the Degradation of Core Protein.PMC126776192023YFC23069027182080BMU2021RCZX0138217225182372236Yang XLiu XLi JLuo ZSun HWang JZhang QSong YfalseAnticodon Engineered Transfer RNA (tRNA<sup>SUAG</sup>) Inhibits Hepatitis B Virus Replication by Promoting the Degradation of Core Protein.Current antiviral drugs targeting the hepatitis B virus (HBV) still face challenges in achieving a functional cure for chronic hepatitis B. Therefore, it is necessary to explore new therapeutic approaches and combined therapy strategies. Anticodon engineered transfer RNA (ACE-tRNA) has been widely applied in the treatment of genetic diseases caused by nonsense mutations. However, its role in antiviral therapy has not been reported yet. In this study, ACE-tRNAs are designed to target the highly conserved stop codon (UAG) of HBV core protein (HBc). All designed ACE-tRNAs can read through the stop codon of HBc. Among them, tRNA^SUAG might promote HBc phosphorylation by introducing a phosphorylatable serine into the C-terminal domain of HBc, thereby potentially reducing HBc levels an2025-01-01T00:00:00Z2025 Dec2026-07-15T12:26:22.708Z2026-07-04T03:13:00.217ZS-EPMC126776194094030510.1002/advs.202503534