The communication between proteomes and the nucleic acid code is key for the expression, modification and distribution of information stored in the genome. This constitutes the basis for all processes of life. It also plays a key role in the development of diseases. The ability to study and model interactions between proteins and nucleic acids in their natural environment is therefore of great importance, for example for the identification and molecular recognition of new drug targets for the treatment of cancer and infectious diseases. Dr. Daniel Summerer from the University of Konstanz deals with the design of proteins and peptides with novel functions. His approach involves the ribosomal incorporation of unnatural amino acids into proteins with the objective of producing proteins with novel functions in living cells.
Biological processes are controlled by the communication between proteins and nucleic acids. The design of new molecular functions at this interface opens up new possibilities for synthetic biology, including the design of new drugs. "The large number of drugs that target cellular nucleic acids, including anti-tumour drugs and several classes of common antibiotics, clearly illustrates the key role of such interactions," explains Dr. Daniel Summerer, chemist at the University of Konstanz. He and his team of researchers are working on the development of new methods to elucidate the function of protein-nucleic acid complexes or to enable new peptide-based drugs that inactivate the function of pathogenic nucleic acids to be designed.
Summerer and his team use strategies that permit the ribosomal biosynthesis of proteins that contain unnatural amino acids in living cells with an expanded genetic code: the proteome of natural organisms is normally built up by a small repertoire of amino acid functions. Natural proteins also suffer from a considerable redundancy in functional chemical groups. "This is quite surprising as the codons could actually store much more information than they do. In principle, it is possible to genetically encode novel chemical functions and integrate them into proteins and endogenous peptides with new functions, specifically designed by scientists," said Dr. Summerer whose approach has already made it possible to integrate numerous unnatural amino acids into proteins. Studies carried out in the department led by Prof. Peter G. Schultz at the Scripps Research Institute in California provided Summerer and his team with evidence that such unnatural amino acids can actually be used to generate novel protein functions. "We were able to control the activity of a DNA-binding transcription factor by way of a synthetic light-controlled transport process between the cell nucleus and the cytoplasm. The synthetic transport process is induced by individual, photoactivatable amino acids," said Summerer.
Summerer and his team will now expand this general strategy in the effort to open up new possibilities for drug design: a huge proportion of currently used drugs with antibacterial, antiviral or tumour-inhibiting effects are natural substances produced by microorganisms. They use complex metabolic pathways to produce nonribosomal peptide (NRP) antibiotics or cytostatics, for example. NRPs are peptide secondary metabolites that are not synthesised by ribosomes. Although the composition of NRPs is largely similar to that of proteins synthesised by ribosomes, they nevertheless have a much higher drug potential than ribosomal proteins. "The repertoire of the chemical modifications and the amino acids used in nonribosomal peptides is much higher than that of ribosomal peptides. This gives rise to peptides that are able to bind to a broad range of different partners. They are also a lot more stable and their affinity and selectivity can even be enhanced by pre-organisation," said Summerer summarising the advantages of NRPs. On the other hand, the biosynthesis pathways of such natural substances are rather complex and not universally found in all organisms. The organisms in which they are found are often difficult to cultivate and the biosynthesis pathways can only be modified with difficulty or not at all. "This makes the production of such drugs rather difficult; and what is even worse is that it makes the efficient design of new drugs impossible, something that is desperately needed as drug resistance is becoming increasingly common," explained Dr. Summerer.
Summerer's alternative approach focuses on expanding the function of ribosomal peptides with key NRP structures by incorporating unnatural amino acids and thus combining the advantages of both biomolecule classes: the strategy enables him to overcome the functional limitations of ribosomal peptides and develop highly efficient strategies for the design of new drugs with novel functions. Summerer and his team are aiming to genetically encode amino acids with larger aromatic groups in order to achieve strong interactions with the aromatic nucleobases of DNA and RNA by what are known as stacking or intercalation interactions. "This binding principle is key for the bioactivity of many natural substances, but does not normally occur in ribosomal proteins. Therefore, it would open up new possibilities for the recognition of nucleic acid targets," summarised Dr. Summerer. The direct genetic encoding of the structures enables the researchers to use the directed molecular evolution methods that are available for peptides and proteins. Rather than having to test drug candidates individually, such methods allow the biosynthesis of hundreds of millions of different potential drugs as well as the enrichment of target molecules. It would also be possible to produce proteins with designer functions in established laboratory organisms.
Dr. Summerer is also interested in designing synthetic endogenous gene switches, which recognise cellular nucleic acids differently than natural proteins. He hopes that such switches will enhance the effect of natural proteins or that unnatural proteins will efficiently inactivate certain points in the genome or transcriptome. If this were successful, Summerer would be able to develop regulatory mechanisms for use in synthetic biology as well as being able to elucidate the function of specific genomic locations. Summerer and his team are looking for industrial cooperation partners in the field of drug testing.
About:Dr. Daniel Summerer studied chemistry in Bonn between 1994 and 2000. His doctorate, which he finished in 2004, focused on the chemical biology of protein-nucleic acid complexes that control the replication of the genome. Summerer then moved on to the Scripps Research Institute, La Jolla, USA where he worked on the expansion of the genetic code by redesigning the RNA translation machinery. He turned to genome research in 2007 when he was appointed Head of Application Development "Enzyme-on-Chip-Technologies" at a Heidelberg-based biotechnology company. He has been a member of the Future College at the University of Konstanz since 2011.
Dr. Daniel SummererUniversity of KonstanzTel.: +49 (0)7531/ 88- 5669E-mail: daniel.summerer(at)uni-konstanz.de