Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Cells by Debio-025, a Novel Cyclophilin Binding Agent

Ptak, Roger G.; Gallay, Philippe; Jochmans, Dirk; Halestrap, Andrew P.; Rüegg, Urs T.; Pallansch, Luke A.; Bobardt, Michael; Béthune, Marie‐Pierre de; Neyts, Johan; Clercq, Erik De; Dumont, Jean-Maurice; Scalfaro, Piétro; Besseghir, Kamel; Wenger, Roland M.; Rosenwirth, Brigitte

doi:10.1128/aac.01324-07

Cited by 109 publications

(104 citation statements)

References 96 publications

(146 reference statements)

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

In mito veritas ?

Kaplan

2008

Med Sci (Paris)

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“…TZM-bl cells were used for both the CCR5 and CXCR4 tropic assays, and the HeLa-CXCR4 cells were used for the control X4 only assays. The PBMCs were freshly isolated and used in viral assays as described previously (56,57). Each assay was conducted in parallel with control compounds AMD3100 (CXCR4 inhibitor; positive control inhibitor for IIIB and negative control inhibitor for Ba-L and ADA) and TAK779 (CCR5 inhibitor; positive control inhibitor for Ba-L and ADA and negative control inhibitor for IIIB) (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Highly Potent Chimeric Inhibitors Targeting Two Steps of HIV Cell Entry

Zhao

Mankowski

Snyder

et al. 2011

Journal of Biological Chemistry

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Blocking HIV-1 cell entry has long been a major goal of anti-HIV drug development. Here, we report a successful design of two highly potent chimeric HIV entry inhibitors composed of one CCR5-targeting RANTES (regulated on activation normal T cell expressed and secreted) variant (5P12-RANTES or 5P14-RANTES (Gaertner, H., Cerini, F., Escola, J. M., Kuenzi, G., Melotti, A., Offord, R., Rossitto-Borlat, I., Nedellec, R., Salkowitz, J., Gorochov, G., Mosier, D., and Hartley, O. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 17706 -17711)) linked to a gp41 fusion inhibitor, C37. Chimeric inhibitors 5P12-linker-C37 and 5P14-linker-C37 showed extremely high antiviral potency in single cycle and replication-competent viral assays against R5-tropic viruses, with IC 50 values as low as 0.004 nM. This inhibition was somewhat strain-dependent and was up to 100-fold better than the RANTES variant alone or in combination with unlinked C37. The chimeric inhibitors also fully retained the antiviral activity of C37 against X4-tropic viruses, and this inhibition can be further enhanced significantly if the target cell co-expresses CCR5 receptor. On human peripheral blood mononuclear cells, the inhibitors showed very strong inhibition against R5-tropic Ba-L strain and X4-tropic IIIB strain, with IC 50 values as low as 0.015 and 0.44 nM, which are 45-and 16-fold better than the parent inhibitors, respectively. A clear delivery mechanism requiring a covalent linkage between the two segments of the chimera was observed and characterized. Furthermore, the two chimeric inhibitors are fully recombinant and are easily produced at low cost. These attributes make them excellent candidates for anti-HIV microbicides. The results of this study also suggest a potent approach for optimizing existing HIV entry inhibitors or designing new inhibitors.Approximately 33 million people are living with HIV, and millions more are infected each year.2 There is currently no vaccine, and treatments usually involve inhibiting viral activity post-infection by inhibiting the HIV protease or reverse transcriptase. More recently, therapies that target other parts of the viral life cycle have been approved, including an HIV integrase inhibitor (3).One of the most promising areas in the fight against HIV/ AIDS has been the development of entry inhibitors, which generally bind to either the viral surface or the human cell surface to stop HIV before it can enter a cell. The HIV surface protein gp120 first makes contact with the human cell surface protein CD4, which causes a conformational rearrangement in gp120, allowing the protein to then bind its co-receptor on the cell surface (either the chemokine receptor CCR5 or CXCR4). During this process, the HIV protein gp41 is exposed, and its fusion peptide enters the cell surface. Toward the end of the infection process, the C-terminal helical trimer folds over to contact the N-terminal trimer of gp41, forming a 6-helix bundle that likely pulls the membranes of the two entities in closer proximity to assist fusion of the vir...

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“…Overall, a number of studies report that chemical inhibition of CypA by CsA and nonimmunosuppressive CsA analogues can inhibit HIV-1 replication [167][168][169]. Furthermore, Alisporivir (Debio-025) is a first-in-class non-immunosuppressive cyclophilin inhibitor to enter clinical trial and has shown promise in the inhibition of HIV-1 [167,170] and HCV [171][172][173].…”

Section: Targeting Cyclophilins In Anti-viral and Anti-cancer Therapymentioning

confidence: 99%

Cyclophilin function in Cancer; lessons from virus replication

Lavin¹

2015

CMP

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Cyclophilins belong to a group of proteins that possess peptidyl prolyl isomerase activity and catalyse the cis-trans conversion of proline peptide bonds. Cyclophilin members play important roles in protein folding and as molecular chaperones, in addition to a wellestablished role as host factors required for completion of the virus life cycle. Members of the cyclophilin family are overexpressed in a range of human malignancies including hepatocellular cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, colorectal cancer and glioblastoma multiforme, however, their precise role in tumourigenesis remains unclear. In recent years, mounting evidence supports a role for prolyl isomerisation during mammalian cell division; a process with striking similarity to plasma membrane remodelling during virus replication. Here we will summarise our current understanding of the role of cyclophilins in cancer. We will review the function of cyclophilins during mammalian cell division and during HIV-1 infection, and highlight common processes involving members of the ESCRT and Rab GTPase families. IntroductionThe interconversion of protein backbone between cis and trans, catalysed by peptidyl prolyl isomerases (PPIases), is an important event that alters protein structure and activity and regulates a wide spectrum of cellular functions in normal physiological processes. For example, isomerisation mediates the spatiotemporal control of fundamental processes including cell cycle progression, cell proliferation and cell death [1][2][3][4]. In recent years, mounting evidence implicates deregulated isomerase activity in a range of age-related pathologies including neurodegeneration, cardiovascular disease and cancer [5]. As a result, isomerases have gained significant interest as therapeutic targets in the treatment of these diseases.

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Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Cells by Debio-025, a Novel Cyclophilin Binding Agent

Cited by 109 publications

References 96 publications

In mito veritas ?

In mito veritas ?

Highly Potent Chimeric Inhibitors Targeting Two Steps of HIV Cell Entry

Cyclophilin function in Cancer; lessons from virus replication

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