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Lausanne, Switzerland

Janssens S.,Ghent University | Tinel A.,Debiopharm SA
Cell Death and Differentiation | Year: 2012

P53-induced protein with a death domain (PIDD) was cloned as a death domain (DD)-containing protein whose expression is induced by p53. It was later described as the core of a molecular platform-activating caspase-2, named the PIDDosome. These first results pointed towards a role for PIDD in apoptosis, in response to DNA damage. Identification of new PIDDosome complexes involved in DNA repair and nuclear factor-κB signaling challenged this early concept. PIDD functions are growing as new complexes and new interaction partners are being discovered, and as additional functions are being revealed. A fascinating feature of PIDD lies within its complex and tight regulation mechanisms, which allow the molecule to fine-tune its different functions: from transcriptional regulation to the expression of different isoforms, and from the interaction with regulatory proteins to an ingenious post-translational cleavage mechanism generating various active fragments with specific functions. Further studies still need to be carried out to provide answers to many unresolved issues and to reconcile conflicting results. This review aims at providing an overview of the current PIDD knowledge status. © 2012 Macmillan Publishers Limited All rights reserved. Source

Wissing E.R.,Howard Hughes Medical Institute | Wissing E.R.,University of Cincinnati | Millay D.P.,Howard Hughes Medical Institute | Vuagniaux G.,Debiopharm SA | Molkentin J.D.,Howard Hughes Medical Institute
Neuromuscular Disorders | Year: 2010

Muscular dystrophy results in the progressive wasting and necrosis of skeletal muscle. Glucocorticoids such as prednisone have emerged as a front-line treatment for many forms of this disease. Recently, Debio-025, a cyclophilin inhibitor that desensitizes the mitochondrial permeability pore and subsequent cellular necrosis, was shown to improve pathology in three different mouse models of muscular dystrophy. However it is not known if Debio-025 can work in conjunction with prednisone, or how it compares against prednisone in mitigating disease in dystrophic mouse models. Here we show that Debio-025 reduced the variations in myofiber cross-sectional areas, decreased fibrosis, and decreased infiltration of activated macrophages more efficiently than prednisone. However the use of prednisone and Debio-025 together had no additional effect on these histopathological indexes. Orally administered Debio-025 also reduced creatine kinase blood levels and improved grip strength in mdx mice after 6. weeks of treatment, and the combination of Debio-025 with prednisone increased muscle function slightly better than prednisone alone. Thus, our results suggest that Debio-025 is as, effective as or slightly better than, prednisone in mitigating muscular dystrophy in the mdx mouse model of disease. © 2010 Elsevier B.V. Source

Bachhav Y.G.,University of Geneva | Bachhav Y.G.,Debiopharm SA | Heinrich A.,Pantec Biosolutions AG | Kalia Y.N.,University of Geneva
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

The aim of the study was (i) to investigate the feasibility of using fractional laser ablation to create micropore arrays in order to deliver proteins into and across the skin and (ii) to demonstrate how transport rates could be controlled by variation of poration and formulation conditions. Four proteins with very different structures and properties were investigated-equine heart cytochrome c (Cyt c; 12.4 kDa), recombinant human growth hormone expressed in Escherichia coli (hGH; 22 kDa), urinary follicle stimulating hormone (FSH; 30 kDa) and FITC-labelled bovine serum albumin (FITC-BSA; 70 kDa). The transport experiments were performed using a scanning Er:YAG diode pumped laser (P.L.E.A.S.E.®; Precise Laser Epidermal System). The distribution of FITC-BSA in the micropores following P.L.E.A.S.E.® poration was visualised by using confocal laser scanning microscopy (CLSM). Porcine skin was used for the device parameter and CLSM studies; its validity as a model was confirmed by subsequent comparison with transport of Cyt c and FITC-BSA across P.L.E.A.S.E.® porated human skin. No protein transport (deposition or permeation) was observed across intact skin; however, P.L.E.A.S.E.® poration enabled total delivery after 24 h of 48.2 ± 8.9, 8.1 ± 4.2, 0.2 ± 0.1 and 273.3 ± 30.6 μg/cm2 for Cyt c, hGH, FSH and FITC-BSA, respectively, using 900 pores/135.9 cm2. Calculation of permeability coefficients showed that there was no linear dependence of transport on molecular weight ((1.6 ± 0.3), (0.1 ± 0.05), (0.08 ± 0.03) and (0.9 ± 0.1) × 10-3 cm/h, for Cyt c, hGH, FSH and FITC-BSA, respectively); indeed, a U-shaped curve was observed. This suggested that molecular weight was not a sufficiently sensitive descriptor and that transport was more likely to be determined by the surface properties of the respective proteins since these would govern interactions with the local microenvironment. Increasing pore density (i.e. the number of micropores per unit area) had a statistically significant effect on the cumulative permeation of both Cyt c (at 100, 150, 300 and 600 pores/cm2, permeation was 11.2 ± 2.4, 15.3 ± 11.8, 33.8 ± 10.5 and 51.2 ± 15.8 4 μg/cm2, respectively) and FITC-BSA (at 50, 100, 150 and 300 pores/cm2, it was 58.5 ± 15.3, 132.6 ± 40.0, 192.7 ± 24.4, 293.3 ± 76.5 μg/cm2, respectively). Linear relationships were established in both cases. However, only the delivery of FITC-BSA was improved upon increasing fluence (53.3 ± 22.5, 293.3 ± 76.5, 329.6 ± 11.5 and 222.1 ± 29.4 μg/cm2 at 22.65, 45.3, 90.6 and 135.9 J/cm2, respectively). The impact of fluence-and hence pore depth-on transport will depend on the relative diffusivities of the protein in the micropore and in the 'bulk' epidermis/dermis. Experiments with Cyt c and FSH confirmed that delivery was dependent upon concentration, and it was shown that therapeutic delivery of the latter was feasible. Cumulative permeation of Cyt c and FITC-BSA was also shown to be statistically equivalent across porcine and human skin. In conclusion, it was demonstrated that laser microporation enabled protein delivery into and across the skin and that this could be modulated via the poration parameters and was also dependent upon the concentration gradient in the pore. However, the role of protein physicochemical properties and their influence on transport rates remains to be elucidated and will be explored in future studies. © 2013 Elsevier B.V. All rights reserved. Source

Rigotti S.,Debiopharm SA | Balmelli C.,Swiss Federal Research Station of Agroscope Changins Wadenswil | Gugerli P.,Swiss Federal Research Station of Agroscope Changins Wadenswil
Potato Research | Year: 2011

The status of the Potato virus Y (PVY) in Swiss seed potato production was investigated in the years 2003 and 2008 by analysing 385 leaf samples of field-grown, suspicious potato plants collected in four representative seed control fields. Serological investigations by ELISA showed that in c.84% of the PVY-positive samples in both years, viruses belonging to the PVYN group were found. All 124 serologically positive PVY samples collected in 2003 and a selection of 81 isolates of 2008 were further typified by molecular tests and by biological assays on tobacco and potato plants. These tests largely confirmed the predominance of the PVYN group and, within this group, the prevalence of recombinant PVYNTN, with 81.4% and 70.4% in 2003 and 2008, respectively. The percentage of PVYN-Wilga (PVYN-Wi) increased from c.6% to 17% between the two years. PVYO was detected only in 10.5% and 4.9% of all molecularly analysed samples in 2003 and 2008, respectively. The persistent predominance of recombinant PVYNTN in Swiss seed potatoes indicates that this strain group is now widespread, representing a considerable threat to Swiss seed potato production. © 2010 EAPR. Source

Aurigene Discovery Technologies Ltd. and Debiopharm S.A. | Date: 2011-02-17

The present invention relates to substituted aromatic bicyclic compounds containing pyrimidine and pyridine rings of formula (I) having the structure as well as pharmaceutically acceptable salts thereof. The compounds of the present invention are useful as tyrosine kinase inhibitors, preferably SRC family kinases (SFKs) inhibitors, in particular as multi SFK/JAK. kinases inhibitors and even preferably as dual c-SRC/JAK kinases inhibitors, thereby inhibiting the STAT3 activation and therefore abnormal growth of particular cell types. Notably, the compounds of the present invention are useful for the treatment or inhibition of certain diseases that are the result of deregulation of STAT3.

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