title: Inhibition of hepatitis E virus replication by peptide-conjugated morpholino oligomers.
abstract: Hepatitis E virus (HEV) infection is a cause of hepatitis in humans worldwide and has been associated with a case-fatality rate of up to 30% in pregnant women. Recently, persistent and chronic HEV infections have been recognized as a serious clinical problem, especially in immunocompromised individuals. To date, there are no FDA-approved HEV-specific antiviral drugs. In this study, we evaluated antisense peptide-conjugated morpholino oligomers (PPMO) designed against HEV genomic sequences as potential HEV-specific antiviral compounds. Two genetically-distinct strains of human HEV, genotype 1 Sar55 and genotype 3 Kernow-C1, isolated from patients with acute and chronic hepatitis, respectively, were used to evaluate inhibition of viral replication by PPMO in liver cells. The anti-HEV PPMO produced a significant reduction in the levels of HEV RNA and capsid protein, indicating effective inhibition of HEV replication. PPMO HP1, which targets a highly conserved sequence in the start site region of ORF1, was also effective against the genotype 3 Kernow-C1 strain in stably-infected HepG2/C3A liver cells. The antiviral activity observed was specific, dose-responsive and potent, suggesting that further exploration of PPMO HP1 as a potential HEV-specific antiviral agent is warranted.
authors.affiliation: VA-MD College of Veterinary Medicine, University of Maryland, College Park, MD, United States.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Nan
authors.affiliation: VA-MD College of Veterinary Medicine, University of Maryland, College Park, MD, United States.
authors.forename: Zexu
authors.initials: Z
authors.lastname: Ma
authors.affiliation: VA-MD College of Veterinary Medicine, University of Maryland, College Park, MD, United States.
authors.forename: Harilakshmi
authors.initials: H
authors.lastname: Kannan
authors.affiliation: Department of Biomedical Science, Oregon State University, Corvallis, OR, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Stein
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States.
authors.forename: Patrick I
authors.initials: PI
authors.lastname: Iversen
authors.affiliation: Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States.
authors.forename: Xiang-Jin
authors.initials: XJ
authors.lastname: Meng
authors.affiliation: VA-MD College of Veterinary Medicine, University of Maryland, College Park, MD, United States; Maryland Pathogen Research Institute, University of Maryland, College Park, MD, United States. Electronic address: zhangyj@umd.edu.
authors.forename: Yan-Jin
authors.initials: YJ
authors.lastname: Zhang
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000032:analysis; D002460:Cell Line; D004337:Drug Carriers / Q000378:metabolism*; D016752:Hepatitis E virus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D008826:Microbial Sensitivity Tests; D060172:Morpholinos / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism*; D012367:RNA, Viral / Q000032:analysis; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D004337:Drug Carriers; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D010455:Peptides; D012367:RNA, Viral
keywords: Antisense; Antiviral; Hepatitis E virus; Morpholino oligomers; PPMO