Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly

Jung-Ah Kang,Yoon Jun Kim,Songwon Kim,Sung-Gyoo Park,Jeong-Hyun Kim,Jeong-Ryul Hwang,Yong-Chul Kim,Mi Sun Jin,Minji Park,Hyun-Jin Park,Sanghyeok Park,Yuri Cho

doi:10.1038/s41467-019-10200-5

Abstract

Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is therefore a serious public health problem. Infected patients are currently treated with nucleoside/nucleotide analogs and interferon α, but this approach is not curative. Here, we screen 978 FDA-approved compounds for their ability to inhibit HBV replication in HBV-expressing HepG2.2.15 cells. We find that ciclopirox, a synthetic antifungal agent, strongly inhibits HBV replication in cells and in mice by blocking HBV capsid assembly. The crystal structure of the HBV core protein and ciclopirox complex reveals a unique binding mode at dimer-dimer interfaces. Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.

Highlights

Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is a serious public health problem
HBV DNA secretion was measured by quantitative PCR using an HBV DNA primer and probe set (Supplementary Table 1); after 3 days’ incubation with ETV, HBV DNA particle secretion was reduced by 42.1 ± 14.1%
The results showed that ciclopirox inhibited HBV DNA secretion most potently (Fig. 1b), possibly by inhibiting HBV capsid assembly

Summary

Introduction

Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is a serious public health problem. Therapies that directly eradicate intrahepatic cccDNA and thereby clear persistent HBV infections This goal has been greatly advanced recently by significant developments in understanding the HBV life cycle, including how the virus enters the host cell[10], how cccDNA is formed[11], and how the HBV capsid is assembled[12]. Protein fluorescence and chromatographic studies did not reveal any structural differences between the wild-type and Cp149-Y132A29, and the compound NVR-010–001-E2 had essentially identical antiviral effects on wild-type and Y132A mutant capsids[28] Both the wild-type and Y132A mutant render human hepatoma HepG2 cells susceptible to TNFα-induced apoptosis by interacting with receptor of activated protein kinase C1 (RACK1)[32]. In many cases, unexpected cytotoxicity has seriously hampered the clinical use of other antiviral compounds[12,22,28,30,34,35]

Methods

Results

Conclusion