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 3 mg kg-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.
|Number of pages||10|
|Journal||Nanomedicine: Nanotechnology, Biology, and Medicine|
|State||Published - 1 Aug 2016|
Bibliographical noteFunding Information:
Funding: This work was supported by a grant from the Technology Innovation Program (MKE 10035159) funded by the Ministry of Knowledge Economy (MKE, Korea) and in part by grants from the National Research Foundation of Korea funded by the Korea government (MSIP) (NRF 2009–0083522, 2010–0025982, 2013–063182, 2014R1A2A2A01005522, and COMPA 2014-11-1672).
© 2016 Elsevier Inc.