Decatransin, a novel natural product inhibiting protein translocation at the Sec61/SecY translocon

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (HUN-7293/cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p/Sec61α1 to confer resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and posttranslationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 homolog. We suggest "decatransin" as the name for this novel decadepsipeptide translocation inhibitor

Femtosecond crystallographic experiment in wide-bandgap LiF crystal

Dachraoui H, Oberer C, Heinzmann U. Femtosecond crystallographic experiment in wide-bandgap LiF crystal. Optics Express. 2011;19(3):2797-2804.We report a femtosecond crystallographic study of the dependence of the free-carries generation to the alignment of a crystalline sample to the laser polarization. The probe pulse transmission exhibits a pi/2 modulation that is shown to be correlated with the direction dependence of the effective electron mass. This observation suggests that nonlinear ionization is the first channel for free electron generation during the laser pulse. Moreover, the temporal evolution of the probe pulse transmission indicates the dominance of the avalanche ionization and that nonlinear ionization provides the initial seed electrons for avalanche." (C)2011 Optical Society of Americ

Direct time-domain observation of laser pulse filaments in transparent media

Dachraoui H, Oberer C, Michelswirth M, Heinzmann U. Direct time-domain observation of laser pulse filaments in transparent media. Physical Review A. 2010;82(4): 043820.The interplay among self-focusing, energy depletion, and plasma formation is fundamental to the understanding of laser-matter interaction. In this article, we present the first direct time-resolved observations of the propagation of intense femtosecond laser pulses experiencing conical emission, self-focusing, self-guiding, beam filamentation, plasma defocusing, and continuum generation in wide-band-gap dielectrics. We demonstrate that continuum generation involves different mechanisms as a function of deposited energy

Interplay between Electronic Correlations and Coherent Structural Dynamics during the Monoclinic Insulator to Rutile Metal Phase Transition in VO2

Dachraoui H, Müller N, Obermeier G, Oberer C, Horn S, Heinzmann U. Interplay between Electronic Correlations and Coherent Structural Dynamics during the Monoclinic Insulator to Rutile Metal Phase Transition in VO2. Journal of Physics. Condensed Matter. 2011;23(43): 435402

Efficient Structure Elucidation of Natural Products in the Pharmaceutical Industry

The procedure of structure elucidation of natural products at Novartis is discussed. Structure elucidation in an industrial environment has to be time efficient, which is achieved by an optimized workflow and a close integration of all analytical methods used in this process. After a preliminary dereplication step based on LC/MS, compounds are delivered to the structure analysis unit. A second dereplication step is based on IR spectroscopic data. Subsequent MS analysis leads to the molecular weight or molecular composition. NMR spectroscopy is finally used for complete structure elucidation, respectively for confirmation of structural suggestions made on the basis of IR and MS data. Challenges like a large number of structure elucidation requests, low amounts of material, variation of sample purity or complexity of structures are faced with modern analytical equipment and high expertise in all disciplines

Attosecond delays in the photoemission from the layered crystals Bi2Te3 and non-centrosymmetric BiTeCl

Resumen del trabajo presentado al Symposium on Surface Science (3S), celebrado en St. Christoph am Arlberg (Austria) del 21 al 27 de febrero de 2016.Peer reviewe

An oral S1P1 antagonist prodrug with efficacy in vivo: discovery, synthesis and evaluation

A prodrug approach to optimize the oral exposure of an S1P1 antagonist for chronic efficacy studies led to the discovery of (S)-2-{[3'-(4-Chloro-2,5-dimethyl-benzenesulfonylamino)-3,5-dimethyl-biphenyl-4-carbonyl]-methyl-amino}-4-dimethylamino-butyric acid methyl ester (BVM924). Due to the steric hindrance and the partial double bond character of the amide group and the resulting large rotational barrier around the amide bond two conformers of (BVM924) can be detected in solution and their equilibration was investigated by UPLC and 1H NMR. Methyl ester prodrug (BVM924) is hydrolyzed in vivo to the corresponding carboxylic acid (BVS819), a potent and selective S1P1 antagonist. Oral administration of the prodrug (BVM924) induces sustained peripheral lymphocyte depletion in rats. In a rat cardiac transplantation model co-administration of a nonefficacious dose of prodrug (BVM924) with a nonefficacious dose of sotrastaurin (AEB071), a protein kinase C inhibitor, or everolimus (RAD001), an mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P1 receptor can be achieved with an S1P1 antagonist generated in vivo after oral administration of its prodrug

Orally bioavailable competitive CCR5 antagonists.

The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models

Decatransin, a novel natural product inhibiting protein translocation at the Sec61/SecY translocon

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (HUN-7293/cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p/Sec61α1 to confer resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and posttranslationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 homolog. We suggest "decatransin" as the name for this novel decadepsipeptide translocation inhibitor

Crystal structure of the Saccharomyces cerevisiae monoglyceride lipase Yju3p

AbstractMonoglyceride lipases (MGLs) are a group of α/β-hydrolases that catalyze the hydrolysis of monoglycerides (MGs) into free fatty acids and glycerol. This reaction serves different physiological functions, namely in the last step of phospholipid and triglyceride degradation, in mammalian endocannabinoid and arachidonic acid metabolism, and in detoxification processes in microbes. Previous crystal structures of MGLs from humans and bacteria revealed conformational plasticity in the cap region of this protein and gave insight into substrate binding. In this study, we present the structure of a MGL from Saccharomyces cerevisiae called Yju3p in its free form and in complex with a covalently bound substrate analog mimicking the tetrahedral intermediate of MG hydrolysis. These structures reveal a high conservation of the overall shape of the MGL cap region and also provide evidence for conformational changes in the cap of Yju3p. The complex structure reveals that, despite the high structural similarity, Yju3p seems to have an additional opening to the substrate binding pocket at a different position compared to human and bacterial MGL. Substrate specificities towards MGs with saturated and unsaturated alkyl chains of different lengths were tested and revealed highest activity towards MG containing a C18:1 fatty acid