• Skip to primary navigation
  • Skip to main content
  • Skip to footer
  • Biblioteca
  • Museu
  • Pessoal
    • Webmail
    • Área de Docentes
    • Área de Não-Docentes
  • Estudantes
    • Webmail
    • Moodle
    • NetP@
    • Escola Doutoral
    • Serviços Académicos
    • Trabalhar no IHMT

IHMT

Instituto de Higiene e Medicina Tropical

  • O Instituto
    • Missão
    • Mensagem do Diretor
    • Órgãos de governo
    • Docentes e investigadores
    • Portal de Denúncias UNL
  • Ensino
    • Mestrados
    • Doutoramentos
    • Cursos de Especialização
    • Formação transversal
    • Cursos de Curta Duração
    • Ensino à Distância
    • Apoio ao Desenvolvimento
    • Serviços académicos
    • NOVA Open Academy
  • Investigação
    • Centro GHTM
    • Unidades de Ensino e de Investigação (UEI)
      • Unidade de Clínica Tropical
      • Unidade de Microbiologia Médica
      • Unidade de Parasitologia Médica
      • Unidade de Saúde Pública Global
      • Serviço de Apoio à Ciência e Comunidade
    • Biobanco
    • BLOODless
    • Centro Colaborador OMS
    • Publicações
  • Serviços e gestão
    • Biblioteca
    • Sistema de Qualidade
    • Estatutos e regulamentos
    • Plano de Atividades
    • Relatório de Atividades
    • Relatório de Gestão
    • Contratos públicos
    • Recursos humanos
      • Concursos e bolsas
        • Concursos – Docentes e Investigadores
        • Concursos – Não Docentes e Não Investigadores
        • Bolsas de Investigação
      • Contratos
      • Avaliação de Desempenho
        • Ciclo Avaliativo
          • Biénio 2021-2022
          • Biénio 2023-2024
        • Conselho Coordenador de Avaliação
        • Comissão Paritária
      • Mobilidade
      • Listas Nominativas
  • Doenças Tropicais
    • Consulta do Viajante
    • Dossiês Informativos
    • Glossário
    • Museu
    • Vídeos
    • MosquitoWeb
  • Comunidade
    • Cooperação e Desenvolvimento
    • Formação
    • Parcerias
  • Contactos
  • Candidaturas
  • pt
    • pt
    • en
Home / Publicações / DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A

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

  • Autores: Bartenschlager R, Berger C, Bobardt M, Chatterji U, Coelmont L, Gallay P, Hanoulle X, Lim P, Lippens G, Neyts J, Paeshuyse J, Snoeck J, Vandamme AM, Vliegen I, Vuagniaux G
  • Ano de Publicação: 2010
  • Journal: PLoS One
  • Link: http://www.ncbi.nlm.nih.gov/pubmed/?term=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 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 <2 weeks with protease or polymerase inhibitors. This indicates a high genetic barrier to resistance for DEB025. Mutation D320E in NS5A was the only mutation consistently selected in the replicon genome. This mutation alone conferred a low-level (3.9-fold) resistance. Replacing the NS5A gene (but not the NS5B gene) from the wild type (WT) genome with the corresponding sequence from the DEB025(res) replicon resulted in transfer of resistance. Cross-resistance with cyclosporine A (CsA) was observed, whereas NS3 protease and NS5B polymerase inhibitors retained WT-activity against DEB025(res) replicons. Unlike WT, DEB025(res) replicon replicated efficiently in CypA knock down cells. However, DEB025 disrupted the interaction between CypA and NS5A regardless of whether the NS5A protein was derived from WT or DEB025(res) replicon. NMR titration experiments with peptides derived from the WT or the DEB025(res) domain II of NS5A corroborated this observation in a quantitative manner. Interestingly, comparative NMR studies on two 20-mer NS5A peptides that contain D320 or E320 revealed a shift in population between the major and minor conformers. These data suggest that D320E conferred low-level resistance to DEB025 probably by reducing the need for CypA-dependent isomerisation of NS5A. Prolonged DEB025 treatment and multiple genotypic changes may be necessary to generate significant resistance to DEB025, underlying the high barrier to resistance.

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

  • Autores: Bartenschlager R, Berger C, Bobardt M, Chatterji U, Coelmont L, Gallay P, Hanoulle X, Lim P, Lippens G, Neyts J, Paeshuyse J, Snoeck J, Vandamme AM, Vliegen I, Vuagniaux G
  • Ano de Publicação: 2010
  • Journal: PLoS One
  • Link: http://www.ncbi.nlm.nih.gov/pubmed/?term=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 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 <2 weeks with protease or polymerase inhibitors. This indicates a high genetic barrier to resistance for DEB025. Mutation D320E in NS5A was the only mutation consistently selected in the replicon genome. This mutation alone conferred a low-level (3.9-fold) resistance. Replacing the NS5A gene (but not the NS5B gene) from the wild type (WT) genome with the corresponding sequence from the DEB025(res) replicon resulted in transfer of resistance. Cross-resistance with cyclosporine A (CsA) was observed, whereas NS3 protease and NS5B polymerase inhibitors retained WT-activity against DEB025(res) replicons. Unlike WT, DEB025(res) replicon replicated efficiently in CypA knock down cells. However, DEB025 disrupted the interaction between CypA and NS5A regardless of whether the NS5A protein was derived from WT or DEB025(res) replicon. NMR titration experiments with peptides derived from the WT or the DEB025(res) domain II of NS5A corroborated this observation in a quantitative manner. Interestingly, comparative NMR studies on two 20-mer NS5A peptides that contain D320 or E320 revealed a shift in population between the major and minor conformers. These data suggest that D320E conferred low-level resistance to DEB025 probably by reducing the need for CypA-dependent isomerisation of NS5A. Prolonged DEB025 treatment and multiple genotypic changes may be necessary to generate significant resistance to DEB025, underlying the high barrier to resistance.

Footer

INSTITUTO DE HIGIENE E
MEDICINA TROPICAL
UNIVERSIDADE NOVA DE LISBOA
Rua da Junqueira, 100 1349-008 Lisboa
T +351 213 652 600
geral@ihmt.unl.pt

Consulta do Viajante e Medicina Tropical
T +351 213 652 630
T +351 213 652 690
T +351 91 182 37 48
T +351 91 182 44 67
medicina.viagens@ihmt.unl.pt

  • Ensino
  • Investigação
  • Medicina Tropical
  • Cooperação
  • Portal de Denúncias UNL

NOVA University of Lisbon Logo

Siga-nos

  • Facebook
  • Instagram
  • LinkedIn
  • Twitter
  • YouTube

Receber a “newsletter”

© Copyright 2025 IHMT-UNL Todos os Direitos Reservados.
  • Universidade Nova de Lisboa
  • Fundação para a Ciência e a Tecnologia

    UIDB/04413/2020
    UIDP/04413/2020

We use cookies to ensure that we give you the best experience on our website. If you continue to use this site we will assume that you are happy with it.Ok