Multiple peptide synthesis to identify bioactive hormone structures

Abstract

Being unable to penetrate the cell membrane, peptide hormones and neuropeptides achieve their effects by interaction with transmembrane receptors which transmit the signal into the cell. G protein-coupled receptors occur ubiquitously in eukaryotes and mediate a multitude of biological functions. The development of drugs targeting these receptors to treat diseases rising from a dysfunction requires the knowledge of ligand-receptor interaction sites as well as of the bioactive conformation of the peptide hormone. In this review article we present concepts and methods in multiple peptide synthesis to determine structural requirements of the ligand for binding to and activation of the corresponding receptor. These include the investigation by alanine and d-amino acid scans to probe the importance of distinct side chains and conformations as well as approaches to obtain conformationally restricted and stabilized distinct structures within the peptide hormone, such as cyclization and introduction of turn mimetics. Examples are taken from several multi-ligand/multi-receptor systems including that of the neuropeptide Y family. Moreover, binding and functional assays that are used to investigate the interaction of ligand and receptor are briefly reviewed. © Springer-Verlag Berlin Heidelberg.