Tim Friedrichson
Dresden University of Technology
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Featured researches published by Tim Friedrichson.
Nature | 1998
Tim Friedrichson; Teymuras V. Kurzchalia
There is some discussion as to whether glycosyl-phosphatidylinositol(GPI)-anchored proteins occur in microdomains in the cell membrane,. These putative microdomains have been implicated in processes such as sorting in polarized cells and signal transduction. Complexes enriched in GPI-anchored proteins, cholesterol and glycosphingolipids have been isolated from cell membranes by using non-ionic detergents: these complexes were thought to represent a clustered arrangement of GPI-anchored proteins,. However, results obtained when clustering of GPI-anchored proteins induced by antibodies or by detergents was prevented support the idea of a dispersed surface distribution of GPI-anchored proteins at steady state. Here we use chemical crosslinking to show that membrane microdomains of a GPI-anchored protein exist at the surface in living cells. This clustering is specific for the GPI-anchored form, as two transmembrane forms bearing the same ectodomain do not form oligomers. Depletion of membrane cholesterol causes the clustering of GPI-anchored proteins to break up, whereas treatment of cells with detergent substantially increases the size of the complexes. We find that in living cells these GPI-anchored proteins reside in microdomains consisting of at least 15 molecules, which are much smaller than those seen after detergent extraction.
European Journal of Medicinal Chemistry | 2010
José Batista; Tim Friedrichson; Georg Schlechtingen; Tobias Braxmeier; Gary Jennings; Jürgen Bajorath
Receptor-mediated signaling events frequently depend on the integrity of their membrane environments. Only a limited number of compounds are currently available that are known or thought to modulate membrane environments and affect signaling events without disrupting membrane structure. Among these are alkylphospholipids including the drug miltefosine that is approved for the treatment of breast cancer and leishmaniasis. In addition, miltefosine has recently been shown to block immunoglobulin E receptor-dependent mast cell activation. On the basis of these findings, we have explored other alkylphospholipids as potential inhibitors of mast cell activation and confirmed the inhibitory activity of five molecules. By comparing the head groups of these alkylphospolipids common pharmacophore features were determined. Through computational screening utilizing this pharmacophore information a new lipid-like inhibitory chemotype was identified that blocked mast cell activation with potency comparable to miltefosine.
Journal of Biomolecular Screening | 2015
Marisa P. McShane; Tim Friedrichson; Angelika Giner; Felix Meyenhofer; Rico Barsacchi; Marc Bickle; Marino Zerial
High-content screening of compound libraries poses various challenges in the early steps in drug discovery such as gaining insights into the mode of action of the selected compounds. Here, we addressed these challenges by integrating two biological screens through bioinformatics and computational analysis. We screened a small-molecule library enriched in amphiphilic compounds in a degranulation assay in rat basophilic leukemia 2H3 (RBL-2H3) cells. The same library was rescreened in a high-content image-based endocytosis assay in HeLa cells. This assay was previously applied to a genome-wide RNAi screen that produced quantitative multiparametric phenotypic profiles for genes that directly or indirectly affect endocytosis. By correlating the endocytic profiles of the compounds with the genome-wide siRNA profiles, we identified candidate pathways that may be inhibited by the compounds. Among these, we focused on the Akt pathway and validated its inhibition in HeLa and RBL-2H3 cells. We further showed that the compounds inhibited the translocation of the Akt-PH domain to the plasma membrane. The approach performed here can be used to integrate chemical and functional genomics screens for investigating the mechanism of action of compounds.
European Journal of Medicinal Chemistry | 2011
José Batista; Georg Schlechtingen; Tim Friedrichson; Tobias Braxmeier; Jürgen Bajorath
The drug miltefosine is a prototypic lipid-like compound thought to modulate membrane environments and thereby indirectly prevent receptor-mediated signaling events. In addition to its primary therapeutic indications in cancer and leishmaniasis, miltefosine has also been shown to block immunoglobulin E receptor-dependent mast cell activation. Miltefosine and other alkylphospholipids that are active in mast cell degranulation assays contain a positively charged nitrogen and a phosphate group that are important for activity. In addition to alkylphospholipids, ceramides are also known to act on membrane environments and inhibit mast cell activation. We have systematically searched a very large compound collection for other lipid-like inhibitors of mast cell activation. Analogs of an initially identified screening hit were synthesized and preliminary SAR information was collected, leading to the identification of sulfoxide and amine oxide containing lipid-like compounds as new inhibitors of mast cell activation. Sulfoxide and amine oxide derivatives were found to be only slightly less active than miltefosine.
Molecular Biology of the Cell | 1999
Mikael Simons; Tim Friedrichson; Jörg B. Schulz; Marina Pitto; Massimo Masserini; Teymuras V. Kurzchalia
Journal of Investigative Dermatology | 2009
Karsten Weller; Metin Artuc; Gary Jennings; Tim Friedrichson; Sven Guhl; Rosaly Vieira dos Santos; Cathleen Sünder; Torsten Zuberbier; Marcus Maurer
Archive | 2005
Tobias Braxmeier; Tim Friedrichson; Wolfgang Fröhner; Gary Jennings; Georg Schlechtingen; Cornelia Schroeder; Hans-Joachim Knölker; Kai Simons; Marino Zerial; Teymuras Kurzchalia
Archive | 2006
Tobias Braxmeier; Tim Friedrichson; Gary Jennings
Archive | 2005
Tobias Braxmeier; Tim Friedrichson; Wolfgang Fröhner; Gary Jennings; Michael Munick; Georg Schlechtingen; Cornelia Schroeder; Hans-Joachim Knölker; Kai Simons; Marino Zerial; Teymuras Kurzchalia
Archive | 2005
Tobias Braxmeier; Tim Friedrichson; Wolfgang Fröhner; Gary Jennings; Georg Schlechtingen; Cornelia Schroeder; Hans-Joachim Knölker; Kai Simons; Marino Zerial; Teymuras Kurzchalia