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Yixin Zhang
Bio-responsive molecular devices and light-responsive drugs
Previous and current research
Developments in biomedicine and biological sciences are always inspired by and based on inventions of novel methods to interfere with living systems, from small organic molecules as drugs, to sophisticated modern biotechnologies. Up-/down-regulation of the concentration of a certain protein or inhibition of its function represent the rationales behind most approaches. An elegant control of such interventions, in dimensions of both time and space, has become very interesting, either as medications with minor side-effect, or as tools in biological research. We are using bioorganic chemistry as the major tool, to discover highly specific binding molecules to proteins of interest, and to design inhibitory systems that can be reversibly switched by light.
- Inhibitors as light-switchable molecular devices. An ideal way for reversible control of bio-molecule is the use of IR light, which is completely non-invasive, site-specific, and transparent to cells and to many tissues. To incorporate an IR responsive chemical moiety into a drug such as immunosuppressive drug cyclosporin A (CsA), we are aiming to reversibly regulate immune system in vitro and in vivo. For in vitro studies, such technology will allow us to probe the dynamics of cellular calcineurin, the immunological target of CsA. The application of this method in vivo will probably lead to novel medication, which can direct drug activity site-specifically by IR light. This novel methodology will also be applied to other drugs, e.g. epothilone and dolastatin, in order to photoswitch their anti-cancer activities.
- Gain-of-function inhibitors targeting protein-protein interfaces. It remains a daunting challenge for drug discovery to target protein-protein interface, though many evidences from molecule biology have suggested that such molecules will lead to more specific inhibitions of individual pathways. Unlike active sites of enzymes, surfaces involved in protein-protein interactions are often not pocket-like, which make it very difficult, if not impossible, to find small organic molecules to fit in with high affinity. However, some natural products, such as CsA and rapamycin are able to block protein surfaces through a gain-of-function mechanism. Therefore, to design and to discover small molecules, which block protein-protein interfaces with a gain-of-function mechanism, represents a new avenue for inhibitor discovery.
- DNA-encoded chemical libraries. This novel technology will be used for discovering gain-of-function inhibitors. Different from traditional drug screening methods, DNA-encoded chemical libraries resemble the approach of nature, using selection and evolution to discover high affinity binders (such as antibodies). In a DNA-encoded chemical library, each organic moiety is covalently conjugated to a DNA strand. While the DNA sequences serve as barcodes, the organic groups represent the phenotype - the potential binding moieties to the protein of interest. The covalent linkage between the phenotype and genotype (DNA sequences) allow us to amplify the enriched compounds with PCR and to identify high affinity binders by high throughput sequencing.
- Self-assembly of nano-structures using pairs of protein-ligand interaction. When the surface of a nano-structure has been coated with photo-switchable chemical groups, the physical and chemical properties of the surface can be modulated by photochemical reactions. Furthermore, because protein-ligand interactions are highly specific, we can use protein heterodimer (e.g. a dimer of two antibody with different recognition specificity) to modulate the interaction of two different nanostructures, whose surfaces have been coated with different chemical groups.
Fig: Scheme: Using IR-light to regulate a pivotal immune signaling pathway reversibly.
Future projects and goals
- Reversible photo-switching of drug activities with IR light. We are interested in drugs that can modulate immune signal transduction pathways (e.g. cyclosporin) and anti-mitotic chemotherapy drugs (e.g. epothilone).
- Discovery of gain-of-function inhibitor by using DNA-encoded chemical libraries and addressable chemical libraries. Addressable chemical library represents the traditional drug discovery strategy via using the screening approach, while DNA-encoded chemical library is a novel drug discovery method via using selection. The combination and comparison of these two methods represent a new avenue for discovering potent inhibitors.
- Macromolecule-drug conjugates. We will design and synthesize drugs conjugated to macromolecules such as nanostructure and antibody. The macromolecules are expected to change the pharmacological properties of the drugs, thus lead to drugs with higher specificity and minor side effects.
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Selected publications
Y. Zhang, F. Erdmann, G. Fischer "Augmented Photoswitching Modulates Immune Signaling" Nature Chemical Biology, 2009 (in press).
Y. Zhang, F. Erdmann, R. Baumgrass, M. Schutkowski, G. Fischer “Unexpected Side Chain Effects at Residue 8 of Cyclosporin A Derivatives Allow Photoswitching of Immunosuppression” J. Biol. Chem. (2005) 4842.
Y. Zhang, R. Baumgrass, M. Schutkowski, G. Fischer “Branches on the alpha-C Atom of Cyclosporin A Residue 3 Result in Direct Calcineurin Inhibition and Rapid Cyclophilin 18 Binding.” ChemBioChem (2004) 5, 1169.
Y. Zhang, S. Fussel, U. Reimer, M. Schutkowski, G. Fischer “Substrate-based design of reversible Pin1 inhibitors.” Biochemistry (2002) 41, 11868.
L. Mannocci, Y. Zhang, J. Scheuermann, M. Leimbacher, G. Bellis, E. Rizzi, C. Dumelin, S. Melkko, Dario Neri “High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries” PNAS (2008) 46, 17670.
S. Melkko, Y. Zhang, C. E. Dumelin, J. Scheuermann, D. Neri “Isolation of High-Affinity Trypsin Inhibitors from a DNA-Encoded Chemical Library” Angew. Chem. (2007) 46, 4671.