The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice

Autor: Michael Bobardt, Philippe Gallay, Daren R. Ure, James Ou, Udayan Chatterji, Daniel J. Trepanier, Robert T. Foster
Rok vydání: 2019
Předmět:
0301 basic medicine
RNA viruses
HBsAg
HIV Infections
Hepacivirus
medicine.disease_cause
Virus Replication
Biochemistry
Cyclophilins
Mice
0302 clinical medicine
Prodrugs
Cyclophilin
Pathology and laboratory medicine
Multidisciplinary
Nucleotides
Hepatitis C virus
Pharmaceutics
virus diseases
Animal Models
Hepatitis B
Medical microbiology
Hepatitis C
3. Good health
Nucleic acids
Liver
Experimental Organism Systems
Toxicity
Viruses
Medicine
030211 gastroenterology & hepatology
Female
Pathogens
Anatomy
Research Article
Hepatitis B virus
Isomerase activity
Science
Cyclosporins
Mice
Transgenic
Mouse Models
DNA replication
Research and Analysis Methods
Antiviral Agents
Microbiology
03 medical and health sciences
Hepatitis B
Chronic
Model Organisms
Drug Therapy
Virology
medicine
Genetics
Animals
Humans
Medicine and health sciences
Hepatitis B Surface Antigens
Biology and life sciences
Flaviviruses
business.industry
Viral pathogens
Organisms
Proteins
Kidneys
Renal System
DNA
medicine.disease
digestive system diseases
Hepatitis viruses
Viral Replication
Microbial pathogens
Mice
Inbred C57BL
030104 developmental biology
Viral replication
DNA
Viral
HIV-1
Animal Studies
Interferons
business
Zdroj: PLoS ONE
PLoS ONE, Vol 14, Iss 6, p e0217433 (2019)
ISSN: 1932-6203
Popis: Hepatitis B virus (HBV) infection is a major health burden worldwide with 240 million chronically infected individuals. Nucleos(t)ide analogs and interferons are the current standards of care due to their suppression of HBV replication, but the treatments rarely eradicate HBV from individuals. Similar to current treatments for human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) patients, improved HBV therapies will require the combination of multiple drugs which target distinct steps of the HBV life cycle. In this study, we tested the potential of a cyclophilin inhibitor, CRV431, to affect HBV replication in transgenic mice. We found that oral treatment with CRV431 (50 mg/kg/day) for a period of 16 days significantly reduced liver HBV DNA levels and moderately decreased serum HBsAg levels. We observed an additive inhibitory effect on liver HBV DNA levels in mice treated with a combination of low doses of CRV431 (10 mg/kg/day) and the nucleotide prodrug, tenofovir exalidex (TXL), (5 mg/kg/day). No toxicity was observed in CRV431-treated mice. Although it is well known that CRV431 neutralizes the peptidyl-prolyl isomerase activity of cyclophilins, its anti-HBV mechanism(s) of action remains unknown. Nevertheless, this study provides the first demonstration of a beneficial effect of a cyclophilin inhibitor in vivo in an HBV transgenic mouse model. Altogether our data reveal the potential of CRV431 to be part of improved new therapies for HBV patients.
Databáze: OpenAIRE
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