Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly.

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.

• Authors: Jung-Ah Kang, Songwon Kim, Minji Park, Hyun-Jin Park, Jeong-Hyun Kim, Sanghyeok Park, Jeong-Ryul Hwang, Yong-Chul Kim, Yoon Jun Kim, Yuri Cho, Mi Sun Jin, Sung-Gyoo Park
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 2184 (05 16 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31097716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• RNA, Viral
• Viral Core Proteins
• Ciclopirox

Topics

• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Capsid (drug effects, metabolism)
• Ciclopirox (chemistry, pharmacology, therapeutic use)
• Crystallography, X-Ray
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Drug Synergism
• Hep G2 Cells
• Hepatitis B virus (drug effects, physiology)
• Hepatitis B, Chronic (drug therapy, pathology, virology)
• Hepatocytes (transplantation, virology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• RNA, Viral (metabolism)
• Transplantation Chimera
• Treatment Outcome
• Viral Core Proteins (chemistry, metabolism)
• Virus Assembly (drug effects)
• Virus Replication (drug effects)