Gearing up for receptor binding: Tryptophan-derived diaryl amino acids in bioactive peptides

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The amino acid L-tryptophan (Trp) is a building block of several neuropeptides that mediate important physiological processes. Trp has an extended pi-system that interacts with the binding pocket of the protein receptors and accounts for much of the binding affinity and selectivity of a peptide. Although structural modifications of the indole ring of Trp mostly cause a dramatic loss of biological activity, a suitable Trp derivative on the other hand can be key to transform a peptide into a drug. Beyond the difficulty of selecting an appropriate Trp mimetic for a certain purpose, the choice is limited because only few preparative protocols are compatible with the sensitive indole side chain of Trp. Therefore, the synthesis of a diverse or even complete group of amino acids representing all possible side chain orientations of Trp is a relevant step towards the idea of the synthesis of the bioactive conformation of Trp-containing peptides.We recently made accessible a new class of Trp-derived amino acids by improving on the synthetic methods that were developed by others for the preparation of beta,beta-diaryl amino acids bearing simple aryl groups. The characteristic feature of the new Trp mimetics is their restricted indole mobility without modifications of the indole ring system. The orientation of the two interlocked aryl propellers of the diaryl amino acid and their interdependent rotational mobility is accessible by NMR spectroscopy. A focus of this project will be laid on the experimental quantification of the relative mobility of the two aryl groups and their response to differing peptide environments. The process known as “steric gearing” prevents the unspecific pi-stacking that is observed with other extended aryl side chains. The correlation between the steric demand of the beta-indoylated amino acids and their influence on the peptide structure will be investigated here. In spite of its potential to control peptide conformation, steric gearing was not systematically investigated as a design principle for bioactive peptides before. In a preliminary experiment we studied two stereoisomers of beta-phenylated Trp which differ only in the relative orientation of their indole group, yet cause complementary selectivities in peptides binding to the ghrelin receptor. In a second testing system, the affinity of ACTH-type peptides for the melanocortin receptor 2 (MC2R) increased by a factor of nearly five when containing one of the beta-indoylated alpha-amino acids. Our cooperation partners will further investigate the promising bioactivities while this research project is dedicated to develop chemical methods to improve the accessibility of Trp-derived beta-branched alpha-amino acids.