Final Report Summary - A2F2 (Beyond Biopolymers: Protein-Sized Aromatic Amide Functional Foldamers)
Nature has evolved ultimate chemical functions using large molecules such as proteins, which carry out enzyme catalysis, and DNA, which is responsible for genetic information storage and duplication. These achievements are based on complex yet remarkably defined structures obtained through the folding of long molecular strands into well-defined shapes stabilized by various attractive and repulsive forces. Nature uses a limited set of building blocks – e.g. twenty amino-acids for proteins and four nucleobases for DNA – with specific abilities to impart well-defined folds. In the last decade, chemists have discovered “foldamers”: molecules that also fold although they have a chemical composition different from that of protein and DNA. It is believed that these non-natural backbones may give access to structures and functions beyond the reach of proteins and nucleic acids, just like nucleic acid and proteins achieve different task due to their distinct chemical composition. The A2F2 projects aimed at developing methods to fabricate and characterize large “foldamers” designed to fold into artificial molecular containers having engineerable cavities and surfaces capable of binding selectively other molecules including sugar derivatives, polymers and proteins. Two major achievements of the A2F2 project are to be reported. One is the design of helical molecular containers that can encapsulate sugars, within a cavity isolated from the surrounding medium, with unprecedented affinity and selectivity. This is remarkable in that the various types of sugars very much resemble each other and are considered extremely difficult to discriminate. Foldamers thus appear as a viable solution to solve the long standing problem of sugar discrimination, a progress that may have application in various disease diagnostics. These findings were reported in the prestigious journal Nature Chemistry. A second major achievement is the development of foldamers the surface of which mimic some surface features of the DNA double helix. The foldamers have been shown to inhibit the activity of proteins that normally bind DNA, but that are high jacked by the foldamers when these are present. Several of these proteins are relevant therapeutic targets in diseases such as AIDS and cancer. New inhibitors of these proteins might thus lead to new therapeutic approaches. These findings were also reported in Nature Chemistry.