1. Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly.
- Author
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Kang JA, Kim S, Park M, Park HJ, Kim JH, Park S, Hwang JR, Kim YC, Jun Kim Y, Cho Y, Sun Jin M, and Park SG
- Subjects
- Animals, Antiviral Agents therapeutic use, Capsid drug effects, Capsid metabolism, Ciclopirox chemistry, Ciclopirox therapeutic use, Crystallography, X-Ray, Disease Models, Animal, Drug Evaluation, Preclinical, Drug Synergism, Hep G2 Cells, Hepatitis B virus drug effects, Hepatitis B, Chronic pathology, Hepatitis B, Chronic virology, Hepatocytes transplantation, Hepatocytes virology, Humans, Male, Mice, Mice, Inbred BALB C, Mice, SCID, RNA, Viral metabolism, Transplantation Chimera, Treatment Outcome, Viral Core Proteins chemistry, Viral Core Proteins metabolism, Virus Replication drug effects, Antiviral Agents pharmacology, Ciclopirox pharmacology, Hepatitis B virus physiology, Hepatitis B, Chronic drug therapy, Virus Assembly drug effects
- 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.
- Published
- 2019
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