Helical aromatic foldamer-based protein recognition
Final Report Abstract
Protein-protein and protein-nucleic acid interactions (PPIs and PNIs) are required for the regulation of cellular life. Inhibitors of these interactions provide useful pharmacological tools and candidates for therapeutic applications. However, PPIs or PNIs involve large molecular surface areas which makes it difficult for drug-like small molecule to act as efficient inhibitors. Artificial proteins or artificial nucleic acids identified by selection technologies are large enough and constitute suitable PPI or PNI inhibitors but they lack some advantages of synthetic molecules in particular their structural and metabolic stability. The research group of Prof. Huc at LMU-Munich has been exploring an alternate approach that combines some benefits of both small molecule and artificial proteins: the design of large - protein-sized - synthetic molecules that adopt stable helical structures ("foldamers”) and that may selectively recognize and bind protein targets. Along this line, recent developments included the design of foldamers that mimic B-DNA negative charge surface and inhibit some PNIs, as well as the demonstration that short foldamers are tolerated as initiators during in vitro peptide translation by the ribosome. Building on this prior knowledge, the project allowed for further development of the DNA-mimic foldamers, including the automation of their synthesis and the integration of design features that make them look like palindromic DNA sequences. A major objective was met under the form of the crystal structure of a complex between a DNA-mimic foldamer and a protein. This milestone will allow for future structure-based design of the foldamers to make them selective of certain PNIs. In the context of a collaboration, the ability of the DNA-mimic foldamers to perturb chromatin assembly was also assessed. Other collaborations yielded the first molecular dynamic simulations of the DNA mimic foldamers using optimized parameters. The project also validated that the tolerance of the ribosome for a foldamer appendage on a translated peptide is high enough to perform mRNA display selection of macrocyclic peptide-foldamer hybrids. A first successful selection allowed for the identification of macrocyclic binders and a crystal structure of a complex between the macrocycle and the protein target was obtained. Again, such a structure constitutes an important milestone – it was a key initial project objective – to further design the macrocycle. Synthetic studies of these macrocycles led to an original method to produce bi-, tri- and tetracycles. The project is now extended in the contact of a Collaborative Research Centre (Chemical Biology of Epigenetic Modifications).
Publications
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Differential Peptide Multi‐Macrocyclizations at the Surface of a Helical Foldamer Template. Angewandte Chemie International Edition, 61(44).
Dengler, Sebastian; Douat, Céline & Huc, Ivan
