title: Liver-targeted antiviral peptide nanocomplexes as potential anti-HCV therapeutics.
abstract: Great success in HCV therapy was achieved by the development of direct-acting antivirals (DAA). However, the unsolved issues such as high cost and genotype dependency drive us to pursue additional therapeutic agents to be used instead or in combination with DAA. The cationic peptide p41 is one of such candidates displaying submicromolar anti-HCV potency. By electrostatic coupling of p41 with anionic poly(amino acid)-based block copolymers, antiviral peptide nanocomplexes (APN) platform was developed to improve peptide stability and to reduce cytotoxicity associated with positive charge. Herein, we developed a facile method to prepare galactosylated Gal-APN and tested their feasibility as liver-specific delivery system. In vitro, Gal-APN displayed specific internalization in hepatoma cell lines. Even though liver-targeted and non-targeted APN displayed comparable antiviral activity, Gal-APN offered prominent advantages to prevent HCV association with lipid droplets and suppress intracellular expression of HCV proteins. Moreover, in vivo preferential liver accumulation of Gal-APN was revealed in the biodistribution study. Altogether, this work illustrates the potential of Gal-APN as a novel liver-targeted therapy against HCV.
authors: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Jinjin
authors: J
authors: Zhang
authors: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Jered C
authors: JC
authors: Garrison
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Larisa Y
authors: LY
authors: Poluektova
authors: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: tbronich@unmc.edu.
authors: Tatiana K
authors: TK
authors: Bronich
authors: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA; Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System Medical Center, 4101 Woolworth Avenue, Omaha, NE 68105, USA. Electronic address: nosna@unmc.edu.
authors: Natalia A
authors: NA
authors: Osna
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D057930:Click Chemistry; D016503:Drug Delivery Systems; D005690:Galactose / Q000737:chemistry; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D058105:Polymerization; D066244:Proton Magnetic Resonance Spectroscopy; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D011092:Polyethylene Glycols; D005690:Galactose
keywords: Anionic poly(amino acid)-based block copolymer; Antiviral peptide nanoparticle; Biodistribution; HCV RNA; HCV proteins; Liver-targeting