Center for Evolutionary Chemical Biology

Molecular properties by combinatorial selection.

Evolution has inspired Combinatorial Science. Combinatorial chemistry allows us to deviate from the confinement of evolution while maintaining a selection pressure. We assemble highly active large libraries of catalytic compounds in the form of peptide-mimetic libraries interacting strongly with transition metals. The assembly is performed on biocompatible beaded resins made from PEG using encoding which allowed incorporation of complex structure and function. Each bead acts as a container with unique catalyst.

Iteratively we produce highly active and selective catalysts towards molecular targets. The building blocks include carbenes, phosphines and heterocycles for binding of catalytic transition metals.

Accessing the structure of pico-moles of active compound isolated by modern screening techniques is inherently difficult. Micro Particle Matrix Encoding is an optical encoding technology which completely detaches the structure elucidation from the compound investigated and provides three structure/activity correlations per second. The encoding is for solid phase chemistry.

The MPM-encoding involves polymer chemistry and combinatorial synthesis of molecular properties. Molecular Velcro constitutes one such property. We identified peptide Velcro molecules by combinatorial screening with encoded libraries of molecules. These Velcro molecules could be used to control adhesion and growth of mammalian cells. They are D-peptides; they interact with the lipid membrane of the cell surface and promote cellular growth. These molecules were identified by studying the adhesion of cells to the surface of beads in a molecule library and they can show stunning effects in cellular control, drug delivery and more.

We also study the molecular interaction by NMR experiments and spectroscopy and characterized the matrix structure formed between iron nanoparticles and linear dextrane fragments in the iron isomaltoside formulation used in the treament of iron deficiency anemia.

Projects

CECB Focus Areas

  • Molecular recognition
  • Organozymes, catalysis and processing
  • GPCR’s
  • Proteolysis
  • Protein “Click” chemistry and folding
  • New chemistries for targeting disease

Molecular bead-bead interaction assays were used to identify small molecules displaying specific electrostatic recognition in water. We developed a range of substrate specific catalysts that hydrolyze peptide bonds. These metallo-peptides were also promising as region-selective catalysts for organic transformations such as Suzuki reactions.

The CECB research group combines technology and research across many scientific disciplines within a combinatorial chemistry platform. The structure of CECB provides technology for the study of complex mechanisms in molecular recognition and biochemical processing from a chemical point of view. CECB aims at understanding molecular recognition, signaling and processing. Typical topics are GPCR-signaling, enzyme and catalyst processing, molecular recognition for controlling cell behavior. The research at CECB is therefore at the interface between chemistry, biology and material sciences.

CECB has developed a range of platform technologies to facilitate the study of recognition, processing and signaling. On-bead assays performed on custom-made biocompatible PEG-resins include solid-phase FRET protease substrate assays, a cells-on-bead assay for investigation of GPCR-activation, a molecular adhesion assay. Combinatorial chemistry is facilitated by optical bead encoding technology, fluorescence activated bead sorting and super high-resolution mass spectrometry

New Chemistries

CECB has developed a reaction for the nucleophilic substitution of non-activated aryl fluorides. The reaction is used in the facile production of some important drugs currently on the market. CECB also developed complex intramolecular cascade click chemistries for synthesis of polycyclic heterocycles.

People

  • Prof. M. Meldal, Ass. Prof. F. Diness
  • 5 postdocs
  • 12 PhD students
  • 4 undergraduates