Difluoromethylornithine, a Decarboxylase 1 Inhibitor, Suppresses Hepatitis B Virus Replication by Reducing HBc Protein Levels.

Binli Mao,Ke Chen,Sidie Pi,Quanxin Long,Yuan Hu,Ailong Huang,Zhuo Wang,Jing Cui

doi:10.3389/fcimb.2020.00158

Abstract

Current treatments of hepatitis B virus (HBV) are limited to Interferon-alpha or the nucleos(t)ide analogs antiviral therapies, and it is crucial to develop and define new antiviral drugs to cure HBV. In this study, we explored the anti-HBV effect of difluoromethylornithine (DFMO), an irreversibly inhibitor of decarboxylase 1(ODC1) on HBV replication. Firstly, we found that polyamines contributed to HBV DNA replication via increasing levels of the HBV core protein (HBc) and capsids. In contrast, depletion of polyamines either by silencing the expression of ODC1 or DFMO treatment, resulted in decreasing viral DNA replication and levels of HBc protein and capsids. Furthermore, we found that DFMO decreased the stability of the HBc protein without affecting mRNA transcription and protein translation. Taken together, our findings demonstrate that DFMO inhibits HBV replication by reducing HBc stability and this may provide a new approach for HBV therapeutics.

Highlights

Despite employing an effective vaccine against Hepatitis B virus (HBV) infection, hepatitis B virus (HBV) remains a major serious health problem worldwide (Lampertico et al, 2017)
ODC1, SRM and spermine synthase (SMS) are rate-limiting enzymes involved in intracellular polyamine biosynthetic pathway (Figure 1A), we initially investigated the expression of these three enzymes in the presence of HBV
We found that the expression of ODC1 and SRM increased both at mRNA and the protein levels by an HBV infection (Figure 1C)

Summary

Introduction

Despite employing an effective vaccine against Hepatitis B virus (HBV) infection, HBV remains a major serious health problem worldwide (Lampertico et al, 2017). There are about 257 million people chronically infected worldwide and over 887,000 death every year according to a WHO report (Revill et al, 2019). There are two approved antiviral treatments for CHB, including interferon-alpha and nucleotide analogs (NAs) (Block et al, 2015). Due to the side effects of interferon-alpha or drug resistance for NAs (Zoulim and Locarnini, 2009), the current therapeutic efficacy is limited. Developing new drugs that directly target either virus or host factors for an efficient CHB treatment is viral and urgent (Mitra et al, 2018)

Methods

Results

Conclusion