Ttrahydroisoquiolie-based peptidomimetics mimickig reverse turn secondary structures

A general approach to the synthesis of peptidomimetics involves the use of small compounds able to mimic or to induce precise aspects of specific peptide secondary structures. Among the secondary structure elements, reverse turns have been shown to be relevant in biomolecular recognition events, mainly due to their frequent localization in the exposed surface of peptides and proteins. For instance, a general “turn” motif is associated with binding of many peptide ligands to over one hundred G protein-coupled receptors (GPCRs). GPCRs are the largest group of membrane-spanning surface receptors on human cells and a promising and still under-developed source of new pharmaceutical targets for treating human diseases or medical conditions. In search of new small peptidomimetics that combine the structural rigidity with the ease of synthetic access, we focused on the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) moiety, a core structure which is known to exhibit affinity towards a wide range of receptors. New peptidomimetics containing the Tic moiety were synthesized in enantiomerically pure form and their conformational features were studied by NMR, IR and molecular modeling techniques. The presence of a reverse turn conformation was observed in all the structures, suggesting the key role of the scaffold as reverse turn inducer.