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International audience; A synthetic helical aromatic oligoamide foldamer receptor with high affinity and selectivity for tartaric acid was subjected to a structure-based evolution of its sequence via mutations, additions and deletions of monomers to produce a new receptor having high affinity and selectivity for malic acid, a guest that differs from tartaric acid by a single oxygen atom. Seven iteratively modified sequences were synthesized. Detailed structural investigations of host-guest complexes were carried out systematically to guide the design of the next generation. A first outcome was a reversal of selectivity of the receptors, with a starting preference for tartaric acid over malic acid of over 10 2 and an ending sequence showing a preference for malic acid over tartaric acid of over 10 2. Another outcome was a very strong enhancement of the affinity for malic acid, despite the fact it has fewer recognition features for binding through polar interactions such as hydrogen bonds. Such level of discrimination between very much resembling guests exemplifies the amenability of foldamers to outstanding achievements in molecular recognition. Altogether, our results demonstrate the viability of a rational receptor design approach that exploits the modularity of foldamer sequences and, in the case of aromatic amide foldamers, their amenability to structural elucidation, their relative ease of synthesis and the predictability of their structure.