Bach A.,Italian Institute of Technology |
Bach A.,Copenhagen University |
Pizzirani D.,Italian Institute of Technology |
Realini N.,Italian Institute of Technology |
And 8 more authors.
Journal of Medicinal Chemistry
Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads. © 2015 American Chemical Society. Source
Gaali S.,Max Planck Institute of Psychiatry |
Gaali S.,Bachem AG |
Feng X.,Max Planck Institute of Psychiatry |
Hahle A.,Max Planck Institute of Psychiatry |
And 3 more authors.
Journal of Medicinal Chemistry
The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51-favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides. This resulted in the first series of pipecolic acid amides, which had much lower molecular weights without affecting FKBP51 selectivity. We discovered a geminally substituted cyclopentyl amide as a preferred FKBP51-binding motif and elucidated its binding mode to provide a new lead structure for future drug optimization. © 2016 American Chemical Society. Source
Giese B.,University of Fribourg |
Kracht S.,University of Fribourg |
Cordes M.,Bachem AG
Nature uses peptide aggregates as soft materials for electron transfer over long distances. These reactions occur in a multistep hopping reaction with various functional groups as relay stations that are located in the side chain and in the backbone of the peptides. © Schweizerische Chemische Gesellschaft. Source
Schillinger E.-K.,University of Ulm |
Schillinger E.-K.,BASF |
Kumin M.,ETH Zurich |
Kumin M.,Bachem AG |
And 5 more authors.
Chemistry of Materials
Within the present work, synthesis and properties of three stereoisomeric hybrid materials consisting of a π-conjugated oligothiophene backbone and a single amino acid (proline), which is attached by click chemistry, are described. The hybrids were in particular investigated regarding their self-assembling behavior in solution. From optical investigations, including circular dichroism spectroscopy, the formation of chiral suprastructures could be deduced and correlated with the stereochemistry of the proline residue. In addition, an elaborate theoretical model of the compounds' self-assembly into suprastructures was developed on the basis of the experimental findings. © 2013 American Chemical Society. Source
Hoff A.,University of Tubingen |
Hoff A.,Trinity College Dublin |
Bagu A.-C.,University of Tubingen |
Andre T.,University of Tubingen |
And 7 more authors.
Cancer Immunology, Immunotherapy
The identification of epitopes that elicit cytotoxic T-lymphocyte activity is a prerequisite for the development of cancer-specific immunotherapies. However, especially the parallel characterization of several epitopes is limited by the availability of T cells. Microarrays have enabled an unprecedented miniaturization and parallelization in biological assays. Here, we developed peptide microarrays for the detection of CTL activity. MHC class I-binding peptide epitopes were pipetted onto polymer-coated glass slides. Target cells, loaded with the cell-impermeant dye calcein, were incubated on these arrays, followed by incubation with antigen-expanded CTLs. Cytotoxic activity was detected by release of calcein and detachment of target cells. With only 200,000 cells per microarray, CTLs could be detected at a frequency of 0.5% corresponding to 1,000 antigen-specific T cells. Target cells and CTLs only settled on peptide spots enabling a clear separation of individual epitopes. Even though no physical boundaries were present between the individual spots, peptide loading only occurred locally and cytolytic activity was confined to the spots carrying the specific epitope. The peptide microarrays provide a robust platform that implements the whole process from antigen presentation to the detection of CTL activity in a miniaturized format. The method surpasses all established methods in the minimum numbers of cells required. With antigen uptake occurring on the microarray, further applications are foreseen in the testing of antigen precursors that require uptake and processing prior to presentation. © 2010 The Author(s). Source