Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly

• Published in: Nature communications Vol. 10; no. 1; pp. 2184 - 14
• Main Authors: Kang, Jung-Ah, Kim, Songwon, Park, Minji, Park, Hyun-Jin, Kim, Jeong-Hyun, Park, Sanghyeok, Hwang, Jeong-Ryul, Kim, Yong-Chul, Jun Kim, Yoon, Cho, Yuri, Sun Jin, Mi, Park, Sung-Gyoo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-05-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/31; 38/22; 38/47; 38/70; 38/77; 631/154; 631/326/22/1295; 631/326/596/1550; 631/535/1266; 64/60; 82/83; 96/63; Analogs; Animals; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Assembly; Capsid - drug effects; Capsid - metabolism; Chronic infection; Ciclopirox - chemistry; Ciclopirox - pharmacology; Ciclopirox - therapeutic use; Cirrhosis; Core protein; Crystal structure; Crystallography, X-Ray; Dimers; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Fungicides; Hep G2 Cells; Hepatitis; Hepatitis B; Hepatitis B virus - drug effects; Hepatitis B virus - physiology; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - pathology; Hepatitis B, Chronic - virology; Hepatocellular carcinoma; Hepatocytes - transplantation; Hepatocytes - virology; Humanities and Social Sciences; Humans; Interfaces; Interferon; Liver cirrhosis; Male; Mice; Mice, Inbred BALB C; Mice, SCID; multidisciplinary; Nucleoside analogs; Nucleosides; Nucleotide analogs; Public health; Replication; RNA, Viral - metabolism; Science; Science (multidisciplinary); Secretion; Transplantation Chimera; Treatment Outcome; Viral Core Proteins - chemistry; Viral Core Proteins - metabolism; Virus Assembly - drug effects; Virus Replication - drug effects; Viruses; α-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10200-5

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.
Current treatments for chronic hepatitis B virus (HBV) infection are not curative. Here, the authors show that an antifungal drug, ciclopirox, inhibits HBV capsid assembly and synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model.