Molecular probes for biology research and drug discovery

While the field of genetics investigates and influences the life's processes by modifying the genes themselves, the field of chemical genetics pursues this goal using chemical compounds that modulate the functioning of the gene and its products (proteins, RNA, etc.). Therefore, chemists, biochemists and biologists from six Max Planck Institutes will work together in the new "Chemical Genomics Centre" in Dortmund in the search for small molecules that allow the study of fundamental life-science processes and the involved biological macromolecules. The Max Planck Society invests a total sum of 5 million euro. The chemical compounds will be designed and made based on natural products analogues, via combinatorial chemistry or rational design and their biological relevance will be tested subsequently in plants, animals and micro-organisms. In this way, molecules shall be identified that are capable of targeting disease relevant proteins or that are candidates for crop protection.

Fig. 1: In a cell-biological assay the cell-morphology is made visible via immune staining of the intracellular F-actin fibres (red) and the cell nucleus (blue). A) Normal MDCK-cells ((Madin-Darby canine kidney epithelial cells) have a round and uniform morphology and grow in layers. B) A cell line (MDCK-f3) grows in a spindle-like, stretched fashion without cell contacts. C) The administration of a special compound (1) results in changes in the appearance of the MDCK-f3 cells. The effect of the mutation is compensated. The reversal of the biological effect, resulting from the cancer gene mutation, allows the determination of the biological target of the chemical compound in the cancer cells. The reversal of the effect shows that the resulting gene product is a potential starting point for a therapy and that compound 1 could serve as a starting point for the development of a drug. D) The administration of compound 2 to the MDCK-f3 cells results in apoptosis of the cell, as can be seen from the swollen round shape of the cells and diminished size of the cell nucleus.

Image: Max Planck Institute for Molecular Physiology In the past decade it became increasingly clear that all biological processes in principal rely on chemical processes and are governed by the structure of the participating molecules and their interactions. Biological processes can be treated as chemical processes and studied in molecular detail. Nevertheless, up to today for only 500 of the over 100.00 proteins encoded by the human genome a chemical compound is known that interacts with and influences the protein. Therefore research following the sequencing of the genome is increasingly focussed on the function of its proteins and their interactions with small molecules (modulators). A new approach for this is Chemical Genomics. What is chemical genomics?

Chemical genomics uses drug-like molecules as modulating ligands for cell-biology research, to clarify for example the function of a certain gene product. For a long time such probe-molecules were only found via serendipitous discoveries and observations. Progress in the automation and parallelisation of chemical synthesis and biological analysis enables the systematic search of modulators of protein function for the investigation of biological phenomena.

Fig. 2: In chemical genomics, a library of molecules is screened for the biological activity of the individual components. If an interesting biological effect results from a particular compound, the target protein will be identified. Inversely, it is possible to evaluate the biological significance of a protein identified via genome research by identifying a substance from a library that binds the protein. With this ligand it is then possible to clarify the role of the protein in a living cell or organism.

Image: Max Planck Institute for Molecular Physiology

The research approach defined as "chemical genetics" (the study of individual gene products using a combination of chemical and biological methods), and "chemical genomics" (the analogous study of the products of a gene family has certain advantages over the genetic methods: The effects of small molecules are generally fast and reversible due to the metabolism and excretion of the molecules. This enables the transient study of proteins. The effect is tuneable, as a varying concentration can result in different degrees of phenotype expression. On top of that, the effect can be initiated and studied at different stages in the development of the organism. Finally, the access to small molecule probes enables anyone to study the effect.

How to find molecular probes for chemical genetics?

Chemical genetics has as a goal to identify substances or molecules that bind with high affinity and specificity to one or a few of the around 100.00 different proteins. Methods developed for combinatorial chemistry enable the synthesis of biological potentially relevant libraries of chemical compounds. An additional source for molecular probes is the isolation or chemical total synthesis of "natural compounds". These are generally complex molecules synthesized by animals or plants and have been optimized for a specific purpose over a period of millions of years via an evolutionary process.

The molecular libraries will subsequently be tested in a variety of biological screens. In these automated tests the screens are monitored via for example optical methods that determine morphological changes of the cells or of complete organisms. Using fluorescence based methods it is possible to localize and quantify special optical markers. Once a substance with a specific biological effect has been identified, it will be used as a starting point for the analysis of the effect and the identification of the involved target protein. Using genome and proteome analysis, the influence of the protein or the active substance on the complete cell will be investigated. With the generation of this knowledge, the substance can be used as a tool for extensive biological studies and its therapeutic relevance can be evaluated. In the end, this may lead to the substance becoming a "lead compound" for the development of new drugs.

Chemical genomics is a powerful new research approach for the fundamental biomedical research. In addition, the approach promises to have a higher efficiency in the search for lead compounds for drug development, because it integrates chemistry and biology already in an early stage in the research process. In this way it permits a fast identification of compounds with high biological relevance.

The Chemical Genomics Centre (CGC) in Dortmund

The Max Planck Society endorses the new interdisciplinary research approach via the founding of an institute-overlapping Chemical Genomics Centre (CGC). Participating institutes are the Max Planck Institute for Molecular Physiology, Dortmund, for Molecular Cell Biology and Genetics, Dresden, for Coal Research, Mülheim, for Plant Breeding Research, Köln, for Psychiatry, München and the Max Planck Institute for Biochemistry, Martinsried. The design and synthesis of the biologically relevant compound libraries based for instance will be pursued in Dortmund and Mülheim. The biological screening and evaluation of the developed molecular tools will be performed in Köln for plants and in Dresden, Martinsried, München and Dortmund for mammalian cell lines.

"We are living in the "post genomics" age, which means that we know and have access to the complete genetic information of not only humans, but also of model organism like the mouse and rat. Also, the genetic information present in important nutrition plants like beans and rice is known. However, to make the promises of the genetics research reality, it is required that biology and chemistry form an alliance", says Herbert Waldmann, director at the Max Planck Institute for Molecular Physiology and coordinator for this multi-institute-spanning initiative of the Max Planck Society. "The CGC is currently the most important research initiative in its field in Europe. Especially the participation of the pharmaceutical industry is unique and enables research projects, normally not pursuable by universities or research institutes."

The build-up of the centre is endorsed by the Max Planck Society with a total of 5 million euro for an initial period of 5 years. This should enable the instalment of several junior research groups and support the research activities at the participating institutes. Furthermore pharmaceutical companies will participate as funding and research partners, financing additional research groups. All research groups will be hosted in the new labs of the Biomedical Centre Dortmund, in the immediate vicinity of the Max Planck Institute for Molecular Physiology.

The research groups supported by the companies will perform basic research on new, currently not sufficiently explored, areas for which, however, great potential for drug development is foreseeable. An example could be the pharmacologically oriented investigation in the interactions between proteins involved in the signal transduction pathways in the cell, leading to new approaches to modulate these interactions.

"The CGC creates a dynamic and inspiring research environment for all participants", states Herbert Waldmann. "Research will start in the summer of 2005 and it is already predictable that this will lead to very interesting and possibly completely unexpected results."

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