DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A

DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. It is currently being evaluated in phase II clinical trials. DEB025 binds to CypA, a peptidyl-prolyl cis-trans isomerase which is a crucial cofactor for...

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Bibliographic Details
Published in:PloS one 2010-10, Vol.5 (10), p.e13687
Main Authors: Coelmont, Lotte, Hanoulle, Xavier, Chatterji, Udayan, Berger, Carola, Snoeck, Joke, Bobardt, Michael, Lim, Precious, Vliegen, Inge, Paeshuyse, Jan, Vuagniaux, Grégoire, Vandamme, Anne-Mieke, Bartenschlager, Ralf, Gallay, Philippe, Lippens, Guy, Neyts, Johan
Format: Article
Language:English
Subjects:
Adaptation
Antiviral Agents
Antiviral Agents - pharmacology
Bioassays
Biochemistry
Biochemistry, Molecular Biology
Cell culture
Cell Line
Clinical trials
Cross-resistance
Cyclophilin A
Cyclophilin A - chemistry
Cyclosporine
Cyclosporine - pharmacology
Cyclosporins
Cytochrome P-450
Dose-Response Relationship, Drug
E coli
Escherichia coli
Genetic aspects
Genomes
Genomics
Genotype & phenotype
Hepacivirus
Hepacivirus - physiology
Hepatitis
Hepatitis C
Hepatitis C virus
Humans
Immunology
Infections
Infectious Diseases
Inhibitors
Interferon
Isomerism
Isomerization
Levels
Life Sciences
Medical research
Mutation
NMR
NS5A protein
Nuclear magnetic resonance
Nucleotide sequence
Peptides
Peptidylprolyl isomerase
Protease
Protease inhibitors
Proteases
Proteinase
Proteinase inhibitors
Proteins
Replication
RNA-directed RNA polymerase
Science
Titration
Virology
Virology/Antivirals, including Modes of Action and Resistance
Virology/New Therapies, including Antivirals and Immunotherapy
Virology/Viral and Gene Regulation
Virus Replication
Virus Replication - drug effects
Viruses
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Summary:DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. It is currently being evaluated in phase II clinical trials. DEB025 binds to CypA, a peptidyl-prolyl cis-trans isomerase which is a crucial cofactor for HCV replication. Here we report that it was very difficult to select resistant replicons (genotype 1b) to DEB025, requiring an average of 20 weeks (four independent experiments), compared to the typically
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0013687