title: A Tat-conjugated Peptide Nucleic Acid Tat-PNA-DR Inhibits Hepatitis B Virus Replication In Vitro and In Vivo by Targeting LTR Direct Repeats of HBV RNA.
abstract: Hepatitis B virus (HBV) infection is a major cause of chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma, all of which are severe threats to human health. However, current clinical therapies for HBV are limited by potential side effects, toxicity, and drug-resistance. In this study, a cell-penetrating peptide-conjugated peptide nucleic acid (PNA), Tat-PNA-DR, was designed to target the direct repeat (DR) sequences of HBV. Tat-PNA-DR effectively inhibited HBV replication in HepG2.2.15 cells. Its anti-HBV effect relied on the binding of Tat-PNA-DR to the DR, whereby it suppressed the translation of hepatitis B e antigen (HBeAg), HBsAg, HBV core, hepatitis B virus x protein, and HBV reverse transcriptase (RT) and the reverse transcription of the HBV genome. Furthermore, Tat-PNA-DR administered by intravenous injection efficiently cleared HBeAg and HBsAg in an acute hepatitis B mouse model. Importantly, it induced an 80% decline in HBV DNA in mouse serum, which was similar to the effect of the widely used clinical drug Lamivudine (3TC). Additionally, a long-term hydrodynamics HBV mouse model also demonstrated Tat-PNA-DR's antiviral effect. Interestingly, Tat-PNA-DR displayed low cytotoxicity, low mouse acute toxicity, low immunogenicity, and high serum stability. These data indicate that Tat-PNA-DR is a unique PNA and a promising drug candidate against HBV.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Zhengyang
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Shisong
authors.initials: S
authors.lastname: Han
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Yange
authors.initials: Y
authors.lastname: Lang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Zeyong
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Xianzheng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao