Foldaptamer: a new molecule "made in IECB"

A novel kind of molecule has been assembled at the IECB in the context of an interdisciplinary collaboration: foldaptamers. The IECB teams of Ivan Huc (biomimetic chemistry) Jean-Jacques Toulmé (molecular biology) have indeed demonstrated in Angewandte Chemie International Edition that it is possible to combine a foldamer with an aptamer.

On the one hand, the team of Ivan Huc (CBMN UMR5248), internationally recognized for its expertise in the chemistry of foldamers - synthetic compounds designed to mimic the ability of natural molecules to fold into well-defined conformations. On the other hand, the group of Jean-Jacques Toulmé (U869), which assembled in 2005 the first French automated platform for the production of aptamers - small strands of oligonucleotides selected for their high affinity with a given target. In 2007, the two IECB groups set up a joint research project which was approved and funded by the French National Agency for Research (ANR).

Therapeutical applications envisionned

"Our idea is simple : by combining the qualities of each compound - chemical diversity for foldamers and biological specificity for aptamers – we may be able to reach targets of therapeutic interest that are not approachable by any of these compounds taken separately” explains Jean-Jacques Toulmé. Foldaptamers could for instance disrupt protein-membrane interactions. In hepatitis C, a viral protein attached to the cell membrane serves as a docking platform for other components of the virus. The molecular assembly envisaged by Ivan Huc and Jean-Jacques Toulmé could recognize this specific protein with the aptamer, and prevent its interaction with the membrane thanks to the foldamer, thus limiting the development of the virus.

"We wanted a happy marriage"

For now, researchers have shown in Angewandte Chemie International Edition that it is possible to form a hybrid foldamer-aptamer structure. But the project was not a foregone conclusion. "Ivan Huc proposed a foldamer consisting of eight units, each one carrying a positive charge. Our aptamers can be considered as pearl necklaces, with each pearl negatively charged. This magnet system is convenient, but it does not guarantee specific interactions. We wanted a happy marriage" Jean-Jacques Toulmé highlights.

Through a combinatorial approach, researchers were able to identify, among 100, 000 billion candidates, the aptamers that specifically bind to the foldamer produced by Ivan Huc. "Aptamers are so specific that they are able to distinguish whether the foldamer helices turn left or right! We also found that the selected aptamers were composed of quadruplex structures, the field of expertise of another project manager of the IECB: Jean-Louis Mergny. We therefore have all the elements on the table to advance this new field of research" concludes Ivan Huc.

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Delaurière, L., Dong, Z., Laxmi-Reddy, K., Godde, F., Toulmé, J.-J. and Huc, I. (2011), Deciphering Aromatic Oligoamide Foldamer–DNA Interactions. Angewandte Chemie International Edition. doi: 10.1002/anie.201106208