title: Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2.
abstract: Host-targeting antivirals have an advantage over direct-acting antivirals in that they have a high genetic barrier to resistance. Here, we describe in vivo anti-hepatitis C virus (HCV) efficacy of a potent siRNA targeting the protein kinase C-related kinase 2 (PRK2), which phosphorylates HCV NS5B RNA-dependent RNA polymerase and promotes HCV replication. PRK2-silencing reduced the phosphorylated NS5B level and resulted in inhibition of NS5B RdRp activity to decrease HCV genome abundance. Systemic administration of lipidoid nanoparticle-formulated PRK2 siRNA (once every three days for a total of three injections at a dose of 3mgkg(-1)) resulted in a 3.72 and 1.96 log10 reduction in serum HCV RNA titer, in mouse subcutaneous and orthotopic xenograft models for HCV replication, respectively. Our results verify the essential role of PRK2 in HCV replication and offer a host-targeting anti-HCV siRNA therapy that might be beneficial for non-responders to current treatment regimens.
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Jae-Su
authors.initials: JS
authors.lastname: Moon
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Song-Hee
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Western Seoul Center of Korea Basic Science Institute, Seoul, Korea.
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Rhee
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Cho
authors.affiliation: Department of Oral Microbiology and Immunology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul, Korea. Electronic address: jwoh@yonsei.ac.kr.
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Oh
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D016174:Hepacivirus; D051379:Mice; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017361:Viral Nonstructural Proteins; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D034741:RNA, Small Interfering; D017361:Viral Nonstructural Proteins
keywords: Antivirals; HCV; Lipidoid; Nanoparticles; PRK2; siRNA