Two side chains in one: A recent paper describes the synthesis of Trp-derived diarylamino acids (Chemical Science, 2019, DOI: 10.1039/C9SC03440D). The groups of A. Beck-Sickinger and S. Els-Heindl successfully investigated their application to control the bioactivity of peptides (in press).

The title compounds Wrf and Wsf were obtained according to the retro syntheic concept of directed C(sp3)–H arylation of phenylalanine and tryptophan, respectively: 

Their characteristic property is a restricted side chain mobility. NMR spectroscopy identifies a single rotamer about the C-C bond as shown in the Newman plot while the C-C-bond of the phenyl group maintains ist high mobility (AA´MM´X spin system). Steric gearing between the two aryl groups prevents unspecific hydrophobic stacking. Therefore the two amino acids are highly soluble and are expected to mediate specific biological effects. 

C:\Users\Prof. Geyer\AppData\Local\Microsoft\Windows\INetCache\Content.Word\Wrf NMR.JPG

The groups of A. Beck-Sickinger and S. Els-Heindl showed that the two synthetic amino acids with inverted side chain stereochemistry Wrf and Wsf induce opposite biological activity. Phe4 is an important part of the activation motif of ghrelin and in short peptide inverse agonists as Lys-trp-Phe-trp-Leu-Leu-NH2, the aromatic core is necessary for the inactivation of the receptor. To restrict the indole/phenyl mobility and simultaneously strengthen the interaction between peptide and receptor, we exchanged the monoaryl amino acid D-Tryptophan (trp) for diaryl amino acids Wrf and Wsf, respectively. 

Both ghrelin analogs showed nanomolar activity, indicating sufficient space to accommodate the additional side chain. In contrast, diaryl amino acids in the inverse agonist had considerable influence on receptor signaling. Whereas Wsf maintains inverse agonism (Lys-trp-Phe-Wrf-Leu-Leu-NH2), ist side chain stereoisomer Wrf induces agonism (Lys-trp-Phe-Wrf-Leu-Leu-NH2). 

geyer@staff.uni-marburg.de