Oligo-arylamide mimics of double stranded DNA – ARYNAMICS

The know-how of the coordinator’s group in the design of molecules having the shape of a strand folded into a helix has been exploited to propose chemical structures having a diameter comparable to that of B-DNA at the surface of which negatively charged groups have been arranged in order to reproduce the arrangement of negatively charged phosphate groups in the B-DNA double helix. A considerable chemical synthesis effort has been devoted to the development of efficient production and purification methods of these DNA mimics. The validation of their helical structures and of their design principles has been carried out through solution state and crystalline state advanced physico-chemical investigations. Their capacity to bind to and interfere with the function of several DNA-binding enzymes has been assessed through molecular biology methods.

New non natural molecules the shape and surface properties of which resemble those of the classical DNA double helix have been designed and synthesized, their structure has been characterized with atomic scale precision. Remarkably and going beyond the initial objectives of the project, these mimics proved to associate to some DNA-binding proteins better than DNA itself, and may constitute decoys able to highjack these proteins from their normal activity.

Since some of these proteins are involved in pathologies such as cancer and aids, the new DNA mimics may be potent candidates to therapeutic applications based on novel mechanism of action.

Owing the real potential applications of the results of the project, these have not been published nor divulgated at conferences until the recent submission of a European patent application entitled « aromatic oligomers, processes for preparing the same and their uses as drugs ». Manuscripts of three publications are in preparation at the time this final report was prepared.

The recent development of genomics and proteomics has allowed the identification of protein-protein interactions and protein-nucleic acid interactions as major classes of therapeutic targets. Among the 22,000 different human proteins, it is estimated that 80% are involved in complexes of two or more proteins. However, protein surfaces involved in interactions with other proteins or with nucleic acids rarely possess well defined grooves or active sites to bind to a small molecule. Standard pharmaceutical strategies making use of small molecule inhibitors are thus poorly adapted to inhibit protein-protein interactions, and new strategies to target protein surfaces are needed. Indeed, medium sized and large molecules are increasingly being considered as therapeutic agents. The potential of large peptides, oligonucleotides and proteins (especially antibodies) is being intensely investigated. In each of theses classes of molecules, examples exist that have made their way to the market for therapeutic use - over 18 antibodies have already been approved. In this context, foldamers, or synthetic oligomers having well defined conformations resembling those of peptides and nucleotides, have emerged as a very promising class of medium sized molecules. Some foldamers have already been shown to recognize a protein surface and to potentially alter its biological function.
This project is based on a new foldamer design recently discovered by one of the participants. The project proposes to improve this design in order to produce and characterize synthetic foldamers capable of inhibiting specific DNA-protein interactions. Such interaction are indeed of immediate relevance in cancer therapy as a large number of DNA-binding proteins are essential to many DNA transactions such as transcription, replication and/or DNA recombination, transactions on which tumor cell growth relies. The project thus aims at significantly advancing the state-of-the-art in foldamer design, in the strategies to recognize protein surfaces, and in approaches to inhibit DNA-binding proteins. Several groups with a long standing experience of bilateral collaborations have been assembled together in this project so as to bring a very wide array of competences in biorganic, supramolecular and synthetic chemistry, in molecular modeling, in structural studies by NMR and x-ray crystallography, in analytical biochemistry, in proteomics, and in molecular pharmacology, all working in different departments of the Bordeaux University campus.

Because of potential patenting opportunities offered by this project, the abstract above, which is meant to become public as per ANR rules, has purposely been written so as not to disclose key concepts or structures.