Using Structural Information of Peptides, Derived from NMR Spectroscopy, in Pharmaceutical Chemistry

Abstract

The significance of information gained from the solution structure of peptides for pharmaceutical research is demonstrated with two examples: the neuropeptide Y (NPY) hormone system and a undecapeptide designed for use as a chemical sensor. In the case of NPY, the structure of the homodimer and the mode of membrane association was determined. Thereby, it was discovered that the membrane/NPY interface is formed by the same hydrophobic residues that constitute the homodimer interface. Furthermore, in the membrane-bound state, the C-terminal helix is stabilized, which is of special functional importance for the C-terminal tetrapeptide. Receptor-subtype specificity of NPY mutants may be explained through pre-orientation of residues relative to the different membrane compartments. In the case of the undecapeptide designed for use in a chemical sensor, structural information from NMR helped us to design and optimize a peptide whose unligated form is unstructured in solution but adopts a unique helical fold upon addition of sulfate. The sulfate binding pocket is formed by the N-terminal first turn.