New heterocyclic scaffolds for conformationally constrained peptide- and peptide mimetic design. (FWOAL459)

Linking an amino acid side chain through a methylene group to a backbone nitrogen is a very efficient method to restrict both the conformation of the side chain and bias that of the main chain. The Tic residue has been particularly successful for the design of potent peptide analogs (e.g. opioids, bradykinin, melanocortin). Moreover, this heterocycle is also found in many peptidomimetics. In contrast, the alternative conformational constraint leading to the 7-membered amino-azepinone structure has found much less applications. This can be partly ascribed to a less easy synthetic accessibility of this heterocycle, compared to Tic. We propose to develop new synthetic methods allowing an easy and general introduction of this type of conformational constraint into bioactive peptides which contain (hetero)aromatic residues. For efficiency reasons, the method should allow solid supported synthesis. We also propose to use this methodology to obtain novel constrained peptides and to design new mimetics of various clinically validated peptides. Moreover, new methods are proposed to prepare novel heterocyclic structures that can function as templates for peptidomimetics. The potential of these methods will be illustrated on a selected number of biological targets.

Keywords:chemistry

Disciplines:Biological sciences