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. 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 designed and evaluated antisense peptide-conjugated morpholino oligomers (PPMO) as potential HEV-specific antiviral compounds. Two genetically-distinct strains of human HEV, genotype 1 Sar55 and genotype 3 Kernow C1, which cause acute and chronic hepatitis, respectively, were used to evaluate PPMO inhibition of viral replication in liver cells. Four anti-HEV PPMOs tested led to a significant reduction in the levels of viral RNA and HEV capsid protein as well as luciferase yield from Sar55 replicons in S10-3 liver cells, indicating an effective inhibition of HEV replication. PPMO HP1, which targets the ORF1 translation initiation region, 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, potent and effective, suggesting that further exploration of HP1 as a potential HEV-specific antiviral agent is warranted