Drug design and screening: from biochemical methods to 3D model system
Previous and Current Research
We are interested in developing chemical methods for biological and medical research and application. Our major focus is drug design and screening. On the one hand, we design and synthesize analogues of drug molecules (e.g. cyclosporin, rapamycin, paciltaxel) and combinatorial chemical libraries (addressable peptide arrays and DNA-encoded chemical libraries). On the other hand, we developed biochemical assays and cell based assays.
a) The biology of cells are often associated with their particular niches. We build up bio-matrices with defined chemical composition to mimic their environment under physiological and pathological conditions, to supply nutrition, to provide signaling, to create polarized conditions, and to, ultimately, allow us to perform cell-based drug screening in 3D model organs.
b) Drug discovery by combining screening and selection methods: Nature develops specific binding molecules (e.g. antibody) using selection, while human discovers small molecule drugs using screening. The emerging field of DNA-encoded chemical library allows us to perform selection of small molecule compounds. We combine both screening and selection approaches, to illustrate their advantages and disadvantages, and to discover high specific inhibitors against proteins of medicinal interest.
c) We design and synthesize analogues of drug molecules. On the one hand, we developed light-switchable compounds as tools for interrogating the dynamics of signal transduction in cells. We are particularly interested in the calcineurin-NFAT pathway and mTOR pathway in immune signaling. On the other hand, we design drug conjugates to improve their pharmacokinetic profile and therapeutic efficacy.
d) Enzymology of cis/trans isomerase. The cis/trans isomerization of peptide bonds represents one of the most fundamental chemical processes governing the biochemical properties of proteins. As the smallest structural change in the scale of biological world, the isomerization and the catalysis of this reaction by isomerases is of great interest, to bridge the dynamics of chemical bonds and the biological functions of the macromolecules.
Future Projects and Goals
- Drug screening using DNA-encoded libraries and addressable arrays.
- Cell-based Drug screening in 3D bio-matrix.
- Light-switchable bio-matrix for cell manipulation.
- Light-switchable immunosuppressive compounds for interrogating signal dynamics.
Methodological and Technical Expertise
- Enzyme inhibition and enzymology
- Peptide synthesis
- DNA modification
- Medicinal chemistry and photochemistry
F. Reddavide, W. Lin, S. Lehnert, Y. Zhang
DNA-encoded Dynamic Chemical Library
Angew. Chem. Int. Ed. Engl., 7924 (2015)
R. Wieduwild, S. Krishnan, K. Chwalek, A. Boden, D. Drechsel, C. Werner, Y. Zhang
Non-covalent Matrix Beads as Microcarriers for Cell Culture.
Angew. Chem. Int. Ed. Engl., 3962 (2015)
M. Thompson, M. Tsurkan, K. Chwalek, M. Bornhauser, M. Schlierf, C. Werner, Y. Zhang
Self-Assembling Hydrogels Crosslinked Solely by Receptor-Ligand Interactions: Tunability, Rationalization of Physical Properties and 3D Cell Culture.
Chem. Eur. J., 3178 (2015)
R. Wieduwild, M. Tsurkan, K. Chwalek, P. Murawala, M. Nowak, U. Freudenberg, C. Neinhuis, C. Werner, Y. Zhang
Minimal Peptide Motif for Non-covalent Peptide-Heparin Hydrogels
J. Am. Chem. Soc., 135(8):2919–22. (2013)
Y. Zhang, F. Erdmann, G. Fischer
Augmented photoswitching modulates immune signaling.
Nature Chem. Biol. 5(10):724–6. (2009)