The non‐immunosuppressive cyclosporin DEBIO‐025 is a potent inhibitor of hepatitis C virus replication in vitro†

Paeshuyse, Jan; Kaul, Artur; Clercq, Erik De; Rosenwirth, Brigitte; Dumont, Jean-Maurice; Scalfaro, Piétro; Bartenschlager, Ralf; Neyts, Johan

doi:10.1002/hep.21102

Cited by 271 publications

(228 citation statements)

References 41 publications

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“…9 These drugs may have an important role to play in therapy, especially in HIV/HCV coinfected patients. Additional studies are needed to determine if the antiviral effect of CsA is clinically relevant, and what resistance mutations, if any, arise in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9] CsA binds molecular chaperones called cyclophilins (CyPs) in cells and inhibits their peptidylproline isomerase activity. 10 The CsA-CyP complex also binds calcineurin and inhibits its activation of T cells.…”

Section: H Epatitis C Virus (Hcv) Chronically Infects Ap-mentioning

confidence: 99%

“…7,12 Certain CsA analogs, such as NIM811 and DEBIO-025, have been shown to have potent anti-HCV activity. 9,13 These CsA analogs retain their ability to bind CyPs, but are no longer recognized by calcineurin. These findings point toward CyP inhibition, not calcineurin inhibition, as being critical for the anti-HCV activity of CsA.…”

Section: H Epatitis C Virus (Hcv) Chronically Infects Ap-mentioning

confidence: 99%

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Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo, we selected for cyclosporine-resistant mutant HCV in vitro. The resulting mutations were mapped to x-ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A (P < 0.0001) or only NS5B (P ‫؍‬ 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo. (HEPATOLOGY

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Section: Discussionmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Chronically Infects Ap-mentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Chronically Infects Ap-mentioning

confidence: 99%

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Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

et al. 2007

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“…Although alisporivir is a structural analog of cyclosporine A, the alisporivir-cyclophilin complex does not inhibit calcineurin, and therefore lacks immunosuppressive activity. [74][75][76] Alisporivir is active against all HCV genotypes and has a high barrier to resistance. 77 A temporary U. S. Food and Drug Administration hold was placed 2012 on the alisporivir development program due to safety concerns arising in alisporivir/PegIFN combination trials.…”

Section: Host-targeting Agentsmentioning

confidence: 99%

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Welzel

Zeuzem

2014

Semin Liver Dis

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The establishment of a robust hepatitis C virus (HCV) cell culture system and subsequent detailed characterization of the HCV life cycle was a key step toward the identification of putative antiviral targets and respective antiviral drugs. 1,2 These include direct-acting antiviral agents (DAAs) such as NS3/4A protease inhibitors, NS5A inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as hosttargeting agents (HTAs) directed against cellular factors involved in viral entry or replication. 3 Trials investigating different drug classes with and without pegylated interferon (PegIFN) and/or ribavirin have rapidly evolved, yielding highly promising sustained virologic response (SVR) rates. 4,5 In regard to the enormous public health impact of HCV infection with an estimated 184 million anti-HCV positive persons worldwide, the recent advances in HCV drug development, together with implementation of improved HCV screening programs, have the potential to substantially reduce the burden of HCV-associated advanced liver disease including hepatocellular carcinoma. 6-9The first-in-class NS3/4A inhibitors telaprevir and boceprevir were approved in 2011. Addition of these drugs to the PegIFN/ribavirin backbone has considerably improved response rates in HCV therapy naïve and experienced patients compared with PegIFN/ribavirin alone. [10][11][12][13] The poor side-effect profile of these IFN-based therapies, however, limits the wide clinical applicability. Proof of the principle that viral clearance can be achieved with an IFN-free DAA combination has fast-tracked design and the conduct of clinical trials investigating IFN-free DAA combinations. 14 Different HCV genotypes and multiple subtypes result in a genotype and subtype-dependent efficacy of many available DAAs. 15,16 Furthermore, viral clearance is challenged by the presence and selection of resistance-associated variants (RAVs). 17,18 Thus, essential prerequisites for DAAs in clinical development comprise a high antiviral efficacy, a broad and at best pan-genotypic activity, as well as a high barrier to resistance. In this respect, nucleos(t)ide polymerase inhibitors display very favorable characteristics. [19][20][21] In addition to a high antiviral efficacy, binding to the highly conserved active site of the RNA-dependent RNA-polymerase (RdRp) and incorporation as active triphosphates into the growing HCV RNA chain terminating its elongation, confers a pan-genotypic activity. Also, the low replication fitness of emergent Keywords ► interferon-free HCV treatment ► direct-acting antiviral agents ► NS3/4A protease inhibitors ► NS5A inhibitors ► non-nucleoside polymerase inhibitors ► host-targeting agents AbstractThe identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The...

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“…D'où l'intérêt de molécules comme Debio-025 qui n'agissent que sur la cible mitochondriale. La pharmacopée a des chances de s'enrichir rapidement car ces molécules sont essentiellement développées comme inhibiteurs de la réplication des virus VHC et VIH [30,31]. Pour l'anecdote, signalons que, dans le même numéro de mars 2008 de Nature Medicine où se trouve l'article de Millay et al [2], on apprend qu'un pas important a été franchi dans le traitement symptomatique de la mucoviscidose [32].…”

Section: Cyclophiline-d Et Dystrophies Musculaires Par Anomalie Du Saunclassified

In mito veritas ?

Kaplan

2008

Med Sci (Paris)

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Les dystrophies musculairesLes dystrophies musculaires (DM) sont des maladies génétiques monogéniques affectant principalement le tissu musculaire strié, qui est progressivement détruit, entraînant une faiblesse musculaire croissante dont la progression est plus ou moins rapide, pouvant à la longue entraîner la mort par insuffisance cardiaque et respiratoire [4]. En fait, cette dénomination recouvre plusieurs dizaines d'entités cliniques distinctes sous-tendues par des défauts siégeant dans une trentaine de gènes déjà identifiés [5], qui spécifient des protéines de fonctions et tion l'espace mitochondrial interne avec le cytosol et aboutit à la mort cellulaire, soit par apoptose s'il ne s'ouvre que par intermittence, soit par nécrose s'il demeure ouvert en permance [15]. Le rôle de CypD dans la pathologie mitochondriale induite par stress oxydatif ou par le Ca 2+ a été élégamment élucidé par des expériences de génomique fonctionnelle, utilisant des souris dont le gène correspondant (Ppif) a été invalidé [16,17]. Mais, puisqu'il s'agit d'une cyclophiline, il existe un autre moyen de neutraliser CypD, c'est la voie pharmacologique par la cyclosporine A (CsA). Rappelons que la CsA est un undécapeptide naturel utilisé depuis 25 ans pour son effet immunosuppresseur. Celui-ci résulte du blocage des cyclophilines cytosoliques qui sont nécessaires pour l'activation de la calcineurine, prélude au déclenchement de la production de certaines interleukines. Or la CypD, qui est strictement mitochondriale, est également une cible pour la CsA. Ceci permet d'envisager un second impact pharmacologique du médicament qui bloquerait la formation du pore PTP, par un mécanisme indépendant de la calcineurine [18]. En substituant sur la molécule de CsA le résidu sarcosine en position 3 par une N-méthyle-D-ala, et le résidu N-méthyle-leucine en position 4 par un reste N-éthyle-val, les chimistes de la firme DebioPharm de Lausanne (Suisse) sont justement parvenus à obtenir un analogue (Debio-025) qui ne cible plus que CypD, ce qui en fait un médi-cament purement mitochondrial, dépourvu de tout effet immunosuppresseur [19] [9][10][11][12]. Ce pore est constitué par l'assemblage de trois protéines : la protéine VDAC (voltage-dependent transporter) située dans la membrane mitochondriale externe, la protéine ANT (adenine nucleotide translocase) dans la membrane mitochondriale interne et la protéine CypD (cyclophiline-D) dans l'espace mitochondrial interne [13,14]. CypD est une peptidyl prolyl-isomérase qui, en se liant à ANT, maintient le pore PTP sous forme ouverte, ce qui met directement en communica-NOUVELLE

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The non‐immunosuppressive cyclosporin DEBIO‐025 is a potent inhibitor of hepatitis C virus replication in vitro†

Cited by 271 publications

References 41 publications

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

In mito veritas ?

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