Prof. Dr. Manfred Schubert-Zsilavecz
Prof. Manfred Schubert-Zsilavecz was born in Austria in 1961. He studied Pharmacy at Karl-Franzens University Graz where he received his Ph.D. in 1989. After spending his postdoc-toral sojourn at Bayreuth University, he joined the faculty of chemistry at Ulm as a Erwin Schrödinger Fellowship(1992-1993). Accepting a position at the Johan Wolfgang Goethe-University Frankfurt, he has been a professor since 1997 at the pharmaceutical chemistry department and currently directs a research group of 10-15 postdoctoral and graduate students. Since 2009 Prof. Manfred Schubert-Zsilavecz is Vicepresident of the Goethe-University. He is member of the scientific board of Phenion Company and member of the board of ZAFES. In 2003 Prof. M.Schubert-Zsilavecz was appointed scientific director of Central Laboratory of German Pharmacist and is currently president of the German Pharmaceutical Society.
Current research projects, group of Prof. Schubert-Zsilavecz
In our group, research focuses on the medicinal chemistry of ligands of nuclear receptors ( Farnesoid X Receptor (FXR), Peroxisome Proliferators-Activated Receptor, PPAR) and the development of analytical techniques for the determination of natural products in biological matrices.
Nuclear receptors are transcription factors that are essential in embryonic development, maintenance of differentiated cellular phenotypes, metabolism an cell death. Dysfunction of nuclear receptor signalling leads to proliferation, reproductive and metabolic diseases such as cancer, infertility, obesity and diabetes.
Pharmaceutical nuclear receptor agonists or antagonists, such as tamoxifen for oestrogen receptors (targeted in breast cancer), thiazolidinediones for peroxisome proliferators-activated receptor-g (PPARg) (targeted in type II diabetes) or dexamethasone for the glucocorticoid receptor (targeted in inflammatory diseases), are among the most commonly used drugs.
Furthermore we are involved in the developement of inhibitors of the microsomal prostaglandin E synthase 1. mPGES-1 constitutes an inducible glutathione-dependent integral membrane protein that catalyzes the oxidoreduction of cyclooxygenase derived PGH2 into PGE2. mPGES-1 has been implicated in a number of human diseases of pathological conditions, such as rheumatoid arthritis, fever, and pain, and is therefore regarded as a primary target for the development of novel anti-inflammatory drugs.
Ongoing research projects (FXR)
The Farnesoid X Receptor (FXR) is a nuclear receptor that acts as a ligand activated transcription factor and is responsible for the regulation of expression of several genes, which play a central role within glucose and lipid homeostasis. Here, especially modulation of the expression of the small heterodimer partner (SHP) or the sterol regulatory element binding protein 1c (SREBP-1c) plays an important role. SHP and SREBP-1c themselves act as transcription factors and influence on prodedures like gluconeogenesis, glycogen synthesis and fatty acid synthesis and degradation. In animal models, FXR activation leads to an improved insulin senisitivity, decreased blood glucose levels and beneficial effects on triglyceride levels in blood. FXR knockout animals show several disturbances within glucose metabolism and lipid homeostasis.
In the last decade, FXR has emerged as an attractive target for drug development for the treatment of diabetes mellitus, dyslipidemia and hepatic disorders like NASH (Non-alcoholic steatohepatitis) in pharmaceutical industry as well as in academia. Much effort has been made to develop new lead structures and some have already been characterized in animal models or in early clinical studies in healthy humans. But until now there is no candidate which has reached later phases of clinical development and promising compounds like GW4064 have not been further developd due to pharmakokinetic or toxicological issues. The need to find new lead structures to follow the promising way of modulating FXR for treatment of several diseases is obvious.
A part of our working group deals with the development and synthesis of FXR modulators and their structure-activity relationships. Therefore, established methods of organic synthesis are used, supported by computational methods like virtual screening and molecular docking. Potentially active compounds first are identified in silico and then synthesized by organic synthesis methods. In the last years, there were several in vitro repotergene assays established in the working group to characterize the synthesized compounds concerning their ability to activate FXR.
Steri R., Kara M., Proschak E., Schubert-Zsilavecz M.
Antidiabetic sulfonylureas modulate Farnesoid X Receptor activation and target gene transcription
Future Medicinal Chemistry 2010; 2 (4): 575-586
Steri R., Schneider P., Klenner A., Rupp M., Schubert-Zsilavecz M., Schneider G.
Target profile prediction: Cross-activation of Peroxisome proliferator-activated Receptor (PPAR) and Farnesoid X Receptor (FXR)
Molecular Informatics 2010; 4: 287-292
Ongoing research projects (PPAR)
Synthesis and pharmacological profiling of selective PPAR modulators (SPPARM)
Evaluation of natural PPAR modulators
Nolte et al. (1998) NATURE 395, 137-143
Ongoing research projects (MPGES1)
Synthesis and pharmacological profiling of selective mPGES-1 inhibitors and dual inhibitors of mPGES-1 and 5-Lipoxygenase
Jegerschöld et al. (2008) PNAS 105, 11110-11115
Ongoing research projects (bioavailability of natural compounds)
In the past, we focused on the development of analytical techniques for the determination of active ingrediants in medicinal plants. Responding to a growing interest, we are focusing now on the determination of these herbal ingredients in biological fluids and tissues (e.g. blood, CNS,...). In the foreground is the question, if active ingredients of Hypericum perforatum like hyperforin, hypericins and flavonoids are able to reach the CNS in adequate concentrations.
Besides Hypericum perforatum other plants (Boswellia serrata, Gingseng, Ginkgo biloba,....) are of current interest.
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