Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2

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• 作者：Jae-Su Moon ; BS^a ; ¹ ; Seung-Hoon Lee ; BS^a ; ¹ ; Song-Hee Han ; MS^a ; Eun-Jung Kim ; MS^a ; Hee Cho ; BS^a ; Wooseong Lee ; BS^a ; Mi-Kyung Kim ; PhD^a ; Tae-Eun Kim ; MS^a ; Hyun-Ji Park ; BS^a ; Jin-Kyu Rhee ; PhD^b ; ² ; Seong-Jun Kim ; PhD^a ; ³ ; Seung-Woo Cho ; PhD^a ; Seung Hyun Han ; PhD^c ; Jong-Won Oh ; PhD^a ; ^{jwoh@yonsei.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HCV ; siRNA ; Lipidoid ; Nanoparticles ; PRK2 ; Antivirals
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：12
• 期：6
• 页码：1489-1498
• 全文大小：1488 K

文摘

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.